# Estimation of cases with dominant inheritance

I am reading [1] and I didn't understand this passage:

All bilateral cases should be counted as hereditary because the proportion of affected offspring closely approximates the 50% expected with dominant inheritance.

Shouldn't the percentage be 75% with dominant inheritance?

[1]: Knudson, Alfred G. "Mutation and cancer: statistical study of retinoblastoma." Proceedings of the National Academy of Sciences 68.4 (1971): 820-823.

It depends on the genotype of P (parents). If only one parent carries the dominant allele, F1 will have the allele 50%.

D = dominant allele, d = recessive allele

P: dd x Dd

F1: Dd 50%, dd 50%

## Dominant Inheritance

When a trait is dominant, only one allele is required for the trait to be observed. A dominant allele will mask a recessive allele, if present. A dominant allele is denoted by a capital letter (A versus a). Since each parent provides one allele, the possible combinations are: AA, Aa, and aa. Offspring whose genotype is either AA or Aa will have the dominant trait expressed phenotypically, while aa individuals express the recessive trait.

One example of a dominantly inherited trait is the presence of a widow’s peak (a V-shape) at the hairline. Let (W) represent the dominant allele, and (w) represent the recessive allele. An individual with a (WW) or (Ww) genotype will have a V-shaped peak at the hairline. Only ww individuals will have a straight hairline. To determine the probability of inheritance of a widow’s peak (or any other dominant trait), the genotypes of the parents must be considered. For example, if one parent is homozygous dominant (WW) and the other is homozygous recessive (ww), then all their offspring will be heterozygous (Ww) and possess a widow’s peak. If both parents are heterozygous (Ww), there is a 75% chance that any one of their offspring will have a widow’s peak (see figure). A Punnett square can be used to determine all possible genotypic combinations in the parents.

A pedigree that depicts a dominantly inherited trait has a few key distinctions. Every affected individual must have an affected parent. Dominantly inherited traits do not skip generations. Lastly, males and females are equally likely to receive a dominant allele and express the trait. In this pedigree both heterozygous and homozygous individuals are affected since the trait is dominant.

Image courtesy of Michael A. Kahn, DDS

## Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene

Background: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required.

Methods: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients.

Results: Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment.

Conclusions: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.

Keywords: A型胰岛素抵抗 Type A insulin resistance insulin receptor (INSR) gene lipodystrophy small for gestational age (SGA) tyrosine kinase domain 小于胎龄儿(SGA) 胰岛素受体(INSR)基因 脂肪营养不良 酪氨酸激酶结构域.

© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

## Autosomal Dominant and Recessive Inheritance

Many important and well-understood genetic diseases are the result of a mutation in a single gene. The online edition of McKusick’s Mendelian Inheritance in Man ( www-ncbi-nlm-nih-gov.easyaccess1.lib.cuhk.edu.hk/Omim/ ) lists nearly 16,000 single genes and more than 8000 single-gene or monogenic traits defined thus far in humans. Of these 24,000 genes and traits, about 23,000 are located on autosomes, nearly 1,300 are located on the X chromosome, and 60 are located on the Y chromosome. The identification of genes that cause monogenic traits has led to new and exciting insights, not only in genetics, but also in the basic pathophysiology of disease.

In this chapter we focus on single-gene disorders caused by mutations on the autosomes. (Single-gene disorders caused by mutations on the sex chromosomes are the subject of Chapter 5 .) We discuss the patterns of inheritance of these diseases in families and factors that complicate these patterns. We also discuss the risks of transmitting single-gene diseases to one’s offspring, because this is usually an important concern for at-risk couples.

## Gregor Mendel’s Contributions

Monogenic traits are also known as mendelian traits, after Gregor Mendel, the 19th-century Austrian monk who deduced several important genetic principles from his well-designed experiments with garden peas. Mendel studied seven traits in the pea, each of which is determined by a single gene. These traits included attributes such as height (tall versus short plants) and seed shape (smooth versus wrinkled). The variation in each of these traits is caused by the presence of different alleles at individual loci.

Several important principles emerged from Mendel’s work. The first, the principle of dominant and recessive inheritance, was discussed in Chapter 3 . Mendel also discovered the principle of segregation, which states that sexually reproducing organisms possess genes that occur in pairs and that only one member of this pair is transmitted to the offspring (i.e., it segregates). The prevalent thinking during Mendel’s time was that hereditary factors from the two parents are blended in the offspring. In contrast, the principle of segregation states that genes remain intact and distinct. An allele for “smooth” seed shape can be transmitted to an offspring in the next generation, which can in turn transmit the same allele to its own offspring. If genes were somehow blended in offspring instead of remaining distinct, it would be impossible to trace genetic inheritance from one generation to the next. Thus the principle of segregation was a key development in modern genetics.

Mendel’s principle of independent assortment was another significant contribution to genetics. This principle states that genes at different loci are transmitted independently. Consider the two loci mentioned previously. One locus can have either the “smooth” or the “wrinkled” allele, and the other can have either the “tall” or the “short” allele. In a reproductive event a parent transmits one allele from each locus to its offspring. The principle of independent assortment dictates that the transmission of a specific allele at one locus (“smooth” or “wrinkled”) has no effect on which allele is transmitted at the other locus (“tall” or “short”).

The principle of segregation describes the behavior of chromosomes in meiosis. The genes on chromosomes segregate during meiosis, and they are transmitted as distinct entities from one generation to the next. When Mendel performed his critical experiments, he had no direct knowledge of chromosomes, meiosis, or genes (indeed, the last term was not coined until 1909, long after Mendel’s death). Although his work was published in 1865 and cited occasionally, its fundamental significance was unrecognized for several decades. Yet Mendel’s research, which was eventually replicated by other researchers at the turn of the 20th century, forms the foundation of much of modern genetics.

Mendel’s key contributions were the principles of dominance and recessiveness, segregation, and independent assortment.

## The Concept of Phenotype

The term genotype has been defined as an individual’s genetic constitution at a locus. The phenotype is what is actually observed physically or clinically. Genotypes do not uniquely correspond to phenotypes. Individuals with two different genotypes, a dominant homozygote and a heterozygote, can have the same phenotype. An example is cystic fibrosis ( Clinical Commentary 4.1 ), an autosomal recessive condition in which only the recessive homozygote is affected. Conversely, the same genotype can produce different phenotypes in different environments. An example is the recessive disease phenylketonuria (PKU, see Chapter 7 ), which is seen in approximately 1 of every 10,000 European-ancestry births. Mutations at the locus encoding the metabolic enzyme phenylalanine hydroxylase render the homozygote unable to metabolize the amino acid phenylalanine. Although babies with PKU are unaffected at birth, their metabolic deficiency produces a buildup of phenylalanine and its toxic metabolites. This process is highly destructive to the central nervous system, and it eventually produces severe mental impairment. It has been estimated that babies with untreated PKU lose, on average, 1 to 2 IQ points per week during the first year of life. Thus the PKU genotype can produce a severe disease phenotype. However, it is straightforward to screen for PKU at birth (see Chapter 13 ), and damage to the brain can be avoided by initiating a low-phenylalanine diet within 1 month after birth. The child still has the PKU genotype, but the phenotype has been profoundly altered by environmental modification.

Cystic fibrosis (CF) is one of the most common single-gene disorders in North America, affecting approximately 1 in 2000 to 1 in 4000 European-American newborns. The prevalence among African-Americans is about 1 in 15,000 births, and it is less than 1 in 30,000 among Asian-Americans. Approximately 30,000 Americans and 70,000 people worldwide are estimated to have this disease.

CF was first identified as a distinct disease entity in 1938 and was termed “cystic fibrosis of the pancreas.” This refers to the fibrotic lesions that develop in the pancreas, one of the principal organs affected by this disorder ( Fig. 4.1 ). Approximately 85% of CF patients have pancreatic insufficiency, in which the pancreas is unable to secrete digestive enzymes, contributing to chronic malabsorption of nutrients. The intestinal tract is also affected, and approximately 15% to 20% of newborns with CF have meconium ileus (thickened, obstructive intestinal matter). The sweat glands of CF patients are abnormal, resulting in high levels of chloride in the sweat. This is the basis for the sweat chloride test commonly used in the diagnosis of this disease. More than 95% of males with CF are sterile due to absence or obstruction of the vas deferens.

The major cause of morbidity and mortality in CF patients is pulmonary disease. Patients with CF have lower airway inflammation and chronic bronchial infection, progressing to end-stage lung disease characterized by extensive airway damage and fibrosis of lung tissue. Airway obstruction and lung injury are thought to be caused by a dehydrated airway surface and reduced clearance, resulting in thick airway mucus. This is associated with infection by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. The combination of airway obstruction, inflammation, and infection leads to destruction of the airways and lung tissue, resulting eventually in death from pulmonary disease in more than 90% of CF patients.

As a result of improved nutrition, airway clearance techniques, and antibiotic therapies, the survival rate of CF patients has improved substantially during the past three decades. Median survival time in the United States is now nearly 40 years. CF has highly variable expression, with some patients experiencing only mild respiratory difficulty and nearly normal survival. Others have much more severe respiratory problems and may survive less than two decades.

CF is caused by mutations in a gene, CFTR, ∗ that encodes the cystic fibrosis transmembrane conductance regulator ( Fig. 4.2 ). CFTR encodes cyclic AMP-regulated chloride ion channels that span the membranes of specialized epithelial cells, such as those that line the bowel and lung. In addition, CFTR is involved in regulating the transport of sodium ions across epithelial cell membranes. The role of CFTR in sodium and chloride transport helps us to understand the multiple effects of mutations at the CF locus. Defective ion transport results in salt imbalances, depleting the airway of water, and producing the thick, obstructive secretions seen in the lungs. The pancreas is also obstructed by thick secretions, leading to fibrosis and pancreatic insufficiency. The chloride ion transport defect explains the abnormally high concentration of chloride in the sweat secretions of CF patients chloride cannot be reabsorbed from the lumen of the sweat duct.

DNA sequence analysis has revealed nearly 2000 different mutations at the CFTR locus. The most common of these, labeled F508del, is a three-base deletion that results in the loss of a phenylalanine residue (F) at position 508 of the CFTR protein. F508del accounts for nearly 70% of all CF mutations. This mutation, along with several dozen other relatively common ones, is assayed in the genetic diagnosis of CF (see Chapter 13 ).

Identification of the specific mutation or mutations that are responsible for CF in a patient can help to predict the severity of the disease. For example, the most severe classes of mutations (of which F508del is an example) result in a complete lack of chloride ion channel production or in channels that cannot migrate to the cell membrane. Patients homozygous for these mutations nearly always have pancreatic insufficiency. In contrast, other mutations (e.g., R117H, a missense mutation) result in ion channels that do proceed to the cell membrane but respond poorly to cyclic AMP and consequently do not remain open as long as they should. The phenotype is thus milder, and patients who have this mutation are less likely to have pancreatic insufficiency. Some males with mild CFTR mutations have only congenital bilateral absence of the vas deferens (CBAVD) but little, if any, lung or gastrointestinal disease. The correlation between genotype and phenotype is far from perfect, however, indicating that modifier loci and environmental factors must also influence expression of the disease (see text). In general there is a reasonably good correlation between genotype and pancreatic function and a more variable relationship between genotype and pulmonary function.

The ability to identify CFTR mutations has led to surveys of persons who have one (heterozygous) or two (homozygous) CFTR mutations, but who do not have cystic fibrosis. They have increased risks for a number of disease conditions, including CBAVD, bronchiectasis (chronic dilatation of the bronchi and abnormal mucus production), and pancreatitis (pancreatic inflammation).

By enhancing our understanding of the pathophysiology of CF, identification of CFTR has opened the possibility of new treatments for this disease. Examples include administration of drugs that cause ribosomes to read through the premature stop codons that account for approximately 7% of CFTR mutations. Other drugs can increase the activity of chloride channels in patients with class III or IV mutations. The first FDA-approved drug for CF treatment, ivacaftor, increases CFTR channel activity in response to ATP. A second FDA-approved drug, lumacaftor, can be used in combination with ivacaftor and has been shown to significantly improve lung function in CF patients homozygous for the common F508del mutation. Gene therapy, in which the normal CFTR gene is placed in viral or other vectors that are then introduced to the patient’s airway (see Chapter 13 ), is also being actively investigated. This strategy, however, has encountered difficulties because viral vectors can induce an inflammatory immune response.

∗ Conventionally the symbol for a gene, such as CFTR , is shown in italics, and the symbol for the protein product is not.

This example shows that the phenotype is the result of the interaction of genotype and environmental factors. It should be emphasized that “environment” can include the genetic environment (i.e., genes at other loci whose products can interact with a specific gene or its product).

The phenotype, which is physically observable, results from the interaction of genotype and environment.

## Basic Pedigree Structure

The pedigree is one of the most commonly used tools in medical genetics. It illustrates the relationships among family members, and it shows which family members are affected or unaffected by a genetic disease. Typically an arrow denotes the proband, the first person in whom the disease is diagnosed in the pedigree. The proband is sometimes also referred to as the index case or propositus (proposita for a female). Fig. 4.3 describes the features of pedigree notation.

When discussing relatives in families, one often refers to degrees of relationship. First-degree relatives are those who are related at the parent–offspring or sibling (brother and sister) level. Second-degree relatives are those who are removed by one additional generational step (e.g., grandparents and their grandchildren, uncles or aunts and their nieces or nephews). Continuing this logic, third-degree relatives would include, for example, one’s first cousins and great-grandchildren.

## Characteristics of Autosomal Dominant Inheritance

Autosomal dominant diseases are seen in roughly 1 of every 200 individuals (see Table 1.3 in Chapter 1 ). Individually each autosomal dominant disease is rather rare in populations, with the most common ones having gene frequencies of about 0.001. For this reason matings between two individuals who are both affected by the same autosomal dominant disease are uncommon. Most often affected offspring are produced by the union of an unaffected parent with an affected heterozygote. The Punnett square in Fig. 4.4 illustrates such a mating. The affected parent can pass either a disease allele or a normal allele to his or her children. Each event has a probability of 0.5. Thus on the average, half of the children will be heterozygotes and will express the disease, and half will be unaffected homozygotes.

Postaxial polydactyly, the presence of an extra digit next to the fifth digit ( Fig. 4.5 ), can be inherited as an autosomal dominant trait. An idealized pedigree for this disease, shown in Fig. 4.6 , illustrates several important characteristics of autosomal dominant inheritance. First, the two sexes exhibit the trait in approximately equal ratios, and males and females are equally likely to transmit the trait to their offspring. This is because postaxial polydactyly is an autosomal disease (as opposed to a disease caused by an X chromosome mutation, in which these ratios typically differ). Second, there is no skipping of generations if an individual has polydactyly, one parent must also have it. This leads to a vertical transmission pattern in which the disease phenotype is usually seen in one generation after another. If neither parent has the trait, none of the children will have it. Third, father-to-son transmission of the disease gene is observed. Although father-to-son transmission is not required to establish autosomal dominant inheritance, its presence in a pedigree rules out some other modes of inheritance (particularly X-linked inheritance see Chapter 5 ). Finally, as we have already seen, an affected heterozygote transmits the disease-causing allele to approximately half of their children. However, because gamete transmission, like coin tossing, is subject to chance fluctuations, it is possible that all or none of the children of an affected parent will have the trait. When large numbers of matings of this type are studied, the proportion of affected children closely approximates 1/2.

Autosomal dominant inheritance is characterized by vertical transmission of the disease phenotype, a lack of skipped generations, and roughly equal numbers of affected males and females. Father-to-son transmission may be observed.

## Recurrence Risks

Parents at risk for producing children with a genetic disease typically want to know the risk, or probability that their future children will be affected. This probability is termed the recurrence risk. If one parent is affected by an autosomal dominant disease and the other is unaffected, the recurrence risk for each child is 1/2 (assuming that the affected parent is a heterozygote, which is nearly always the case). It is important to keep in mind that each birth is an independent event, as in the coin-tossing examples. Thus even if the parents have already had a child with the disease, their recurrence risk remains 1/2. Even if they have had several children, all affected (or all unaffected) by the disease, the law of independence dictates that the probability that their next child will have the disease is still 1/2. Although this concept seems intuitively obvious, it is commonly misunderstood by the lay population. Further aspects of communicating risks to families are discussed in Chapter 15 .

The recurrence risk for an autosomal dominant disorder is 50%. Because of independence, this risk remains constant no matter how many affected or unaffected children are born.

## Autosomal Recessive Inheritance

Like autosomal dominant diseases, autosomal recessive diseases are individually fairly rare in populations. As shown previously, heterozygous carriers for recessive disease alleles are much more common than affected homozygotes. Consequently the parents of individuals affected with autosomal recessive diseases are usually both heterozygous carriers. As the Punnett square in Fig. 4.7 demonstrates, one-fourth of the offspring of two heterozygotes will be unaffected homozygotes, half will be phenotypically unaffected heterozygous carriers, and one-fourth will be homozygotes affected with the disease (on average).

## Characteristics of Autosomal Recessive Inheritance

Fig. 4.8 is a pedigree showing the inheritance pattern of an autosomal recessive form of albinism that results from mutations in the gene that encodes tyrosinase, a tyrosine-metabolizing enzyme. ∗ The resulting tyrosinase deficiency creates a block in the metabolic pathway that normally leads to the synthesis of melanin pigment. Consequently the affected individual has very little pigment in the skin, hair, and eyes ( Fig. 4.9 ). Because melanin is also required for the normal development of the optic fibers, persons with albinism can also display nystagmus (rapid uncontrolled eye movement), strabismus (deviation of the eye from its normal axis), and reduced visual acuity. The pedigree demonstrates most of the important criteria for distinguishing autosomal recessive inheritance ( Table 4.1 ). First, unlike autosomal dominant diseases in which the disease phenotype is seen in one generation after another, autosomal recessive diseases are usually observed in one or more siblings, but not in earlier generations. Second, as in autosomal dominant inheritance, males and females are affected in equal proportions. Third, on average, one-fourth of the offspring of two heterozygous carriers will be affected with the disorder. Finally, consanguinity is present more often in pedigrees involving autosomal recessive diseases than in those involving other types of inheritance (see Fig. 4.8 ). The term consanguinity (Latin, “with blood”) refers to the mating of related persons. It is sometimes a factor in recessive disease because related persons are more likely to share the same disease-causing alleles. Consanguinity is discussed in greater detail later in this chapter.

∗ This form of albinism, termed tyrosinase-negative oculocutaneous albinism (OCA1), is distinguished from a second, milder form termed tyrosinase-positive oculocutaneous albinism (OCA2). OCA2 is typically caused by mutations in a gene on chromosome 15, whose protein product is thought to be involved in the transport and processing of tyrosine and tyrosinase.

Autosomal recessive inheritance is characterized by clustering of the disease phenotype among siblings, but the disease is not usually seen among parents or other ancestors. Equal numbers of affected males and females are usually seen, and consanguinity may be present.

## Autosomal Dominant Examples

Autosomal dominant examples can relate to skin, hair, and eye color, the risk of developing certain diseases, and even inherited behaviors associated with neurological traits. While many diagrams show the chances or probabilities of inheriting brown, blue, or green eyes from both parents, eye color is the result of countless alleles and not always predictable. For clearer examples, it is better to concentrate on single mutant alleles as this rules out the influence of other genetic factors.

Chromosome four hosts the huntingtin protein gene (HTT gene) that contains between 10 and 35 repetitions of a specific piece of code known as the CAG trinucleotide repeat. In patients with Huntington’s disease, these repetitions occur at least 40 times. This might be due to inheritance, but it has since been discovered that repeat expansions can change in size in the same or successive generations. Just because you have the HTT gene does not mean that you will develop Huntington’s disease. This particular disease has already be mentioned as being an autosomal dominant disorder with a twist when researchers discover what triggers increased repeat expansions, they will be able to halt or even cure their associated illnesses. Repeat expansions cause many genetic disorders.

As an autosomal dominant disease, only one parent needs to present with a trait and pass it on to the next generation. In the diagram above, the huntingtin gene of the mother is represented by a capital letter H. No mutation in the HTT gene (hh) is represented by the unshaded squares the gray-shaded boxes indicate mutation of the HTT gene (Hh).

It may be that the parent with the mutated HTT has less CAG trinucleotide repeats and does not present with the symptoms of Huntington’s, but the dynamic nature of this gene may mean that higher repetitions occur at a later point in life, or during the life of any child or children this parent has.

It is clear in the diagram that half of the offspring of a Hh and hh parent are at risk of the mutated trait (Hh). Diagrams that show inherited traits are often referred to as punnet squares or pedigree charts.

Another popular example in the field of autosomal dominance is polycystic kidney disease, where multiple cysts develop in the kidneys and reduce their ability to filter waste products from the blood.

As with Huntington’s disease, autosomal dominant polycystic kidney disease (ADPKD) is the product of a single parent passing on the disorder. In this case, a single mutated copy of the PKD1 or PKD2 gene causes the disease. PKD1 is found on chromosome 16 PDK2 on chromosome 4. A relatively newly discovered gene on chromosome 11 can produce combined polycystic kidney and liver disease. Also as with Huntington’s, some cases of ADPKD are the result of a new mutation. Unlike Huntington’s, it is also possible to have autosomal recessive forms of polycystic kidney disease (ARPKD).

## Discussion

Herein, we have proposed to identify the mode of inheritance in a continuous scale using the degree of dominance h, which is based on the ratio of the odds ratio of the co-dominant contrast divided by the absolute value of the odds ratio of the additive contrast. Numerical results suggest that the h index captures the essence of what should be understood by genetic model or mode of inheritance. A meticulous analysis has been performed to check performance against an a priori model where we already know that a mutant allele is associated to a disease and also the degree of dominance of this allele. Simulations also show that the degree of dominance h is affected by deviations from HWE, although the bias is more serious when there is population stratification. In these cases the findings should be interpreted carefully, and adjustments for departures from HWE might be applied [1, 10]. Furthermore, power for detecting significance for h when the study conforms HWE rule increases with the degree of dominance and to some extent is related to the mutant allele frequency.

The empirical study we carried out showed the degree of dominance may sufficiently indicate the mode of inheritance. Any degree of dominance exists when the co-dominant contrast is significant irrespectively to the additive contrast. The co-dominant and additive contrasts show a reverse pattern in h and, also important, in the range of over- or under-dominance the additive contrast is non-significant. In general, candidate-gene studies have a tendency to lack power for detecting dominance arising from weak genetic contributions of common variants though, large genome-wide association studies have been undertaken recently and an effort to create consortia for data sharing is initiated [21, 22]. An underpowered GAS will underestimate the significance of the orthogonal contrasts and, therefore, the value of h. Nevertheless, the power to detect the significance of the co-dominant contrast and/or the additive contrast is the same with the power to detect a significance association between the genotype distribution and the disease using a logistic regression with explanatory variable the genotype with three levels. The proposed index may be applied to both types of GAS (candidate-gene studies and GWAS) in the same way (of course the recording of the genotype distribution is a necessary condition). However, in testing the significance of the orthogonal contrasts for an individual variant of a GWAS a multiplicity adjustment should be considered.

In order to avoid the obstacle of the multiple genetic contrasts, Zintzaras [4] proposed the concept of generalized odds ratio (ORG) for analyzing and meta-analyzing GAS. ORG is a single statistic that summarizes the magnitude and significance of the association without considering the hash of possible contrasts, and provides a straightforward interpretation of the results in GAS. The ORG utilizes the complete genotype distribution and provides an estimate of the magnitude of the association, given that the mutational load and the phenotype (bi-allelic or multi-allelic) are treated as a graded exposure (case-control or disease progression). Specifically, ORG express the probability of a subject being diseased relative to probability of being free of disease, given that the diseased subject has a higher mutational load than the non-diseased. ORG with values greater than one suggests that disease is proportional to increased genetic exposure and inversely proportional for values less than one. Thus, the application of ORG may overcome the shortcomings of multiple model testing or erroneous model specification and provides an alternative and robust way for genetic association testing.

Regarding meta-analysis, model-free approaches have been proposed to estimate the genetic model [6, 23]. However, we would like to stress that merging studies with potentially heterogeneous modes of inheritance should be avoided since we could entirely miss the true biological meaning underlying disease susceptibility. The application of our proposed method to identify the mode of inheritance warrants further investigation in this context. Although the methodology proposed here is straightforward, a Bayesian approach for implementing the method might be more desirable, especially when there is prior estimation of the magnitude and accuracy of the genetic risk effect and the degree of dominance [24, 25].

Although all of Mendel’s pea plant characteristics behaved according to the law of independent assortment, we now know that some allele combinations are not inherited independently of each other. Genes that are located on separate, non-homologous chromosomes will always sort independently. However, each chromosome contains hundreds or thousands of genes, organized linearly on chromosomes like beads on a string. The segregation of alleles into gametes can be influenced by linkage, in which genes that are located physically close to each other on the same chromosome are more likely to be inherited as a pair. However, because of the process of recombination, or “crossover,” it is possible for two genes on the same chromosome to behave independently, or as if they are not linked. To understand this, let us consider the biological basis of gene linkage and recombination.

Homologous chromosomes possess the same genes in the same order, though the specific alleles of the gene can be different on each of the two chromosomes. Recall that during interphase and prophase I of meiosis, homologous chromosomes first replicate and then synapse, with like genes on the homologs aligning with each other. At this stage, segments of homologous chromosomes exchange linear segments of genetic material (Figure 8.18). This process is called recombination, or crossover, and it is a common genetic process. Because the genes are aligned during recombination, the gene order is not altered. Instead, the result of recombination is that maternal and paternal alleles are combined onto the same chromosome. Across a given chromosome, several recombination events may occur, causing extensive shuffling of alleles.

Figure 8.18 The process of crossover, or recombination, occurs when two homologous chromosomes align and exchange a segment of genetic material.

When two genes are located on the same chromosome, they are considered linked, and their alleles tend to be transmitted through meiosis together. To exemplify this, imagine a dihybrid cross involving flower color and plant height in which the genes are next to each other on the chromosome. If one homologous chromosome has alleles for tall plants and red flowers, and the other chromosome has genes for short plants and yellow flowers, then when the gametes are formed, the tall and red alleles will tend to go together into a gamete and the short and yellow alleles will go into other gametes. These are called the parental genotypes because they have been inherited intact from the parents of the individual producing gametes. But unlike if the genes were on different chromosomes, there will be no gametes with tall and yellow alleles and no gametes with short and red alleles. If you create a Punnett square with these gametes, you will see that the classical Mendelian prediction of a 9:3:3:1 outcome of a dihybrid cross would not apply. As the distance between two genes increases, the probability of one or more crossovers between them increases and the genes behave more like they are on separate chromosomes. Geneticists have used the proportion of recombinant gametes (the ones not like the parents) as a measure of how far apart genes are on a chromosome. Using this information, they have constructed linkage maps of genes on chromosomes for well-studied organisms, including humans.

Mendel’s seminal publication makes no mention of linkage, and many researchers have questioned whether he encountered linkage but chose not to publish those crosses out of concern that they would invalidate his independent assortment postulate. The garden pea has seven chromosomes, and some have suggested that his choice of seven characteristics was not a coincidence. However, even if the genes he examined were not located on separate chromosomes, it is possible that he simply did not observe linkage because of the extensive shuffling effects of recombination.

## Genetics Teaching Box

Why is there so much variation within families? Why don’t siblings with the same biological parents look identical to each other? This Digital Teaching Box contains classroom-tested, NGSS-aligned resources for teaching the sources of genetic variation and how traits are inherited.

Author & Affiliation
Daisy Yeung
Teacher-in-Residence
Exploratorium Teacher Institute

Time Estimate
Four weeks

Concepts Covered
Mendelian genetics
Molecular genetics
Genes x environment

### Resource 1: Developing an Initial Model to Explain Genetic Variation Within Families

Through group activities and class discussions, give students the chance to observe genetic variation in biological families and begin to draw initial models of what might cause it.

Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• This is the anchoring phenomenon for the whole unit. As such, student groups should return to these models and update them at least once at the end of the unit, and preferably another time halfway through. Ways in which students can make their changes more explicit can be found here.
• As students are investigating the family photos, be open to any background information they bring in. Accept all noticings with no judgement. Discussion questions might include:
• What do you notice?
• What are the similarities between parents and offspring? What are the differences?
• What questions do you have?

### Resource 2: Skin Color Spectrum

Focus students’ investigation into variation on one particular complex trait: skin color. Students compare the skin colors of their inner and outer arms and discuss what could be causing any variation they observe.

Hilleary Osheroff
Exploratorium Teacher Institute

Resource Type
Image, Classroom Activity

Teaching Notes

• Most human traits are not controlled by single genes, but by multiple genes and alleles combined with multiple environmental factors. Many genetics units begin with a survey of human traits that are supposedly Mendelian, that is, controlled by single genes and presented as binary (attached vs. free earlobes, blue vs. non-blue eyes, freckles vs. no freckles). I suggest that starting a genetics unit with a complex trait that involves multiple genes and alleles with both genetic and environmental factors is a more scientifically accurate representation of the inheritance patterns of most traits in living things, may help students avoid the commonly held misconception that most traits are Mendelian, and may help students appreciate and consider the significant environmental effects that contribute to most human traits.
• Since this is an introductory activity to help frame the unit, accept all ideas without judgement.
• Cut the colored image into strips (A–F) and fasten together with a brad. Have students identify which swatches best match the colors of their inner upper arms and the colors of their outer lower arms.
• Discussion questions:
• What did you notice?
• Did your skin color change by number or by letter or both?
• Are there any patterns of change within the class?
• What do you think causes your inner arm to be that particular color?
• What do you think causes your outer arm to be that particular color?
• Why might some people have a greater difference between the two? Why might some people have no difference between the two?
• This will hopefully get at the idea that skin color has both genetic and environmental components, which ties in with the next activity.

### Resource 3: Genetics vs. Environment Spectrum

In an extension of Resource 2, continuing the framing for the unit, students discuss which traits they believe to be caused more by genetic factors, which are caused more by environmental factors, and which are a combination of both.

Resource Type
Classroom Activity

Teaching Notes

• This framing activity helps to elicit student ideas about what causes variations in humans. Accept all ideas without judgement.
• Six to eight different traits is a good number to promote discussion. When choosing the traits you want to discuss, think about which ones are appropriate for your students. It’s best to tailor the list to the backgrounds and interests of your students.
• Discussion questions:
• What do you notice?
• Can you tell me why you decided to place your dot there?
• Are there any similarities between the more “genetic” traits and the more “environmental” traits?
• Think about the model you drew earlier—are there any variations you see that may have an environmental factor? How would you know?

### Resource 4: Mendelian Genetics Introduction Videos

Introduce Gregor Mendel and his contributions to the study of inheritance using these videos.

Resource Type
Videos

Teaching Notes

• These videos may be used as part of a flipped classroom model to introduce further activities that reinforce key concepts and vocabulary.
• While much of this teaching box allows students to figure out the science behind genetics, it may be too much of a leap for students to be given Mendel’s pea plant data and come to the same conclusions as he did. This part of the unit may require some direct instruction, especially in regards to key vocabulary and the use of Punnett squares. These videos will need to be supplemented with other activities—there are many options available online and in traditional genetics units.
• While few human traits follow the same inheritance patterns as those that were discovered by Mendel, he did discover some key features of inheritance that ring true for all traits (the concepts of segregation and independent assortment, that the alleles from each parent aren’t blended or altered in the offspring, and that all sexually reproducing organisms follow these same inheritance rules). While important for the discovery of other key concepts, dominance and recessiveness are often overemphasized in genetics units—I advise spending less time on them and providing more opportunities for students to investigate other patterns of inheritance.

### Resource 5: A New Inherited Human Traits Survey

Students investigate human traits that are commonly introduced in biology classes as examples of monogenic inheritance patterns (two possible alleles: one dominant, one recessive). They analyze data about the inheritance patterns of each trait to determine which, if any, are truly monogenic in nature and would fit the inheritance patterns that Mendel observed in his pea plants.

Hilleary Osheroff, Exploratorium Teacher Institute
John McDonald, Myths of Human Genetics

Resource Type
Classroom Activity, Assessment

Teaching Notes

• This is a continuation of the simple dominant/recessive inheritance patterns that Mendel discovered with his pea plant experiments and can be used as an assessment. Prior to this activity, students should be familiar with dominant and recessive alleles and their inheritance patterns. An understanding of Punnett squares may be useful as well.
• The activity can be introduced the same way as a typical survey of human traits in a typical biology class: have students determine which combination of traits they have, then compare and contrast their combinations of traits with those of their classmates.
• Discussion questions:
• What do you notice?
• If two people have the same combination of traits, what might that mean, if anything?
• Notice that there were only two options for each trait—were there any traits where it was difficult for you to decide between the two options? Tell me why.
• Do you think you can determine which traits are dominant and which traits are recessive?
• Can you think of a better way to collect the data for some of these traits than just giving two options?
• Encourage students to explain their reasoning using Punnett squares.
• The only two traits that may show indications of a similar dominant/recessive inheritance pattern are asparagus pee smell and earwax texture. The others, although presented as binary, are more complicated.
• Which traits showed the same inheritance patterns as the pea plants?
• What about the other traits? What do you notice?
• What questions do you have about human inheritance after looking at the data?
• Do all traits follow the same pattern of inheritance as Mendel’s pea plants? If not, what are other possible patterns of inheritance?

### Resource 6: Mother & Child Reunion

Investigate other patterns of inheritance, including codominance, incomplete dominance, and multiple-allele traits, focusing on the genetics of blood type.

Daisy Yeung, Exploratorium Teacher Institute
Karen Kalumuck, Human Body Explorations: Hands-On Investigations of What Makes Us Tick

Resource Type
Classroom Activity

Teaching Notes

• Most students are very interested in blood, blood transfusions, and blood types, and you may want to collect their questions before beginning this activity.
• Prior to the investigation, you should introduce the inheritance of multiple-allele traits. This requires some direct instruction—see the PowerPoint linked to the Resource Link button above.
• Because each “patient’s” blood is the same, but antibodies are different, I recommend creating stations for each patient so that the blood and antibodies stay together. It’s also important to stress to students to avoid cross-contamination, otherwise the results will be inaccurate.
• After the investigation, it may be of interest to students to discuss blood transfusions and what blood type may be donated to which recipient.
• Discussion questions:
• What is different about the way blood type is inherited from the way pea plant traits are inherited?
• What is the same?
• What do you think these inherited “factors” actually are? What are they made of? How do they work?

### Resource 7: DNA Structure Building Challenge

Investigate and build a model of the structure of DNA, the genetic material that’s passed from one generation to the next. Students can use historical data as pieces of evidence that accumulate over time, resulting in the discovery of DNA’s double helix structure.

Tammy Cook-Endres, Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• Before this activity, you may want to do a DNA extraction lab to provide some context for students and to emphasize the importance of using models in science (the DNA you extract is visible with the naked eye, but the double helix is still too small to see).
• This activity illustrates the nature of science and how scientific ideas change as evidence accumulates over time. It is helpful to show these changes by encouraging students to come up with multiple possible models with the initial clues, then eliminate possibilities as more evidence is presented.
• Most students have seen a double helix before, so it is important to emphasize prior to this activity that, although the end result will be a double helix, they should base their models only on the evidence that is available.

### Resource 8: Sizing Up—Genetics Version

Introduce students to the organization of genetic material (alleles, genes, chromosomes) and the relative sizes of molecules and cells involved in inheritance.

Karen Kalumuck & Tammy Cook-Endres, Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• Students often struggle with finding a context for abstract concepts like DNA, genes, proteins, and cells that are too small to see (therefore, students often use these words interchangeably to mean the same thing, when they aren’t). This activity provides a more relatable image of how molecular structures compare.
• This HHMI video may also help students visualize the molecules involved. It is important to emphasize that DNA and chromosomes are large, complex molecules that look different when viewed at different scales. This is especially important because different models are used to represent these molecules, which can be very confusing for students.
• Discussion questions:
• What have we figured out so far about DNA?
• What questions do you still have?
• Ideally, we want students to land on the question: We know that DNA is the molecule that’s passed from parent to offspring, but how does that happen? And how does that lead to genetic variation in families?

### Resource 9: Meiosis Chromosome Pairing Activity

Simplify the complex structure of chromosomes to allow students to compare and contrast the differences between genes, alleles, and homologous chromosomes.

Daisy Yeung, Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• Provide each student with a chromosome and ask them to find their match. Their initial instinct is often to find someone with an identical chromosome. They will come to realize that some colors don’t match up exactly (i.e., pink with red, orange with brown), but the sizes of the matching chromosomes and the locations and numbers of the alleles are the same. You can lead a discussion to address these noticings:
• How did you find your match?
• Why do you think there are always two matching chromosomes? (For an additional challenge, you may incorporate X and Y chromosomes, in which case, you could ask if anyone couldn’t find a match)

### Resource 10: Modeling Meiosis

Let students design a pathway to represent the steps of meiosis given the starting and ending cells in the process. They’ll repeat the process three times, each time with added complexity. Introduce students to segregation, independent assortment, and crossing over.

Hilleary Osheroff, Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• You may choose to give students a more open-ended prompt or a more guided one for the first model, but challenge them to draw a model of at least two possible pathways.
• If you want to provide more restrictions for their model, you may tell students that they may only do two things: duplicate chromosomes or split cells in half.
• This first model can be used to help inform their subsequent models (one model may end up fitting better with the additional data to come, which is why it’s important that students draw out at least two options to start)
• Compare the initial cells with the final cells in each round. How are they different? How are they the same?
• Based on what you modeled in this activity, why do siblings not look identical even though they have the same biological parents?
• Ideally, after this activity, students would land on a question that sounds like: Now we know why the DNA in siblings is never the same, but how does the information in DNA become a physically formed trait that we can see, like eye color or earwax texture?

### Resource 11: Breakfast Proteins

Use a colored cereal bracelet built from a code as an analogy for the central dogma.

Exploratorium Teacher Institute Snack Page

Resource Type
Classroom Activity

Teaching Notes

• This activity could be used as an initial shared experience for students to refer back to as they explore the central dogma, or it could be used as an assessment afterward to check for understanding.
• Discussion questions (if using as initial phenomenon):
• Describe the steps of the process for building your cereal bracelet.
• How did you know how to build the correct cereal bracelet?

### Resource 12: Protein Synthesis Simulation

Let students try a few ways of simulating the steps of protein synthesis (transcription and translation).

Resource Type
Classroom Activity

Teaching Notes

• Some direct instruction about transcription and translation is necessary before beginning these simulations. Here are some helpful web resources:
• HHMI video of transcription
• HHMI video of translation
• Amoeba Sisters: Protein Synthesis video
• Protein synthesis online interactives: University of Utah, Exploratorium
• In what ways was this simulation an accurate representation of the steps of protein synthesis?

### Resource 13: Pencil Transferase

Investigate the connection between a protein’s structure and its function.

Jeanne Ting Chowning, The American Biology Teacher

Resource Type
Classroom Activity

Teaching Notes

• It may be helpful to supplement this activity with other protein structure and function activities if proteins have not been discussed in detail in prior units of study. Resources for these additional activities are not provided here, but the following Web searches are a good place to start:
• Lactase persistence
• Catalase
• Amylase
• What is different?
• Look around the room. Is there anything that everyone’s pencil transferases have in common?
• If something were to go wrong with the shape of your pencil transferase (mutate), where would that mutation have the largest impact on your protein’s ability to function? Where would that mutation have less of an impact?

### Resource 14: Mutate Your Name

Investigate the connection between a protein’s structure and its function.

Daisy Yeung, Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• I allow my students to choose any name as long as it is 5–8 letters long. You have the option to add restrictions or have every student use the same name for the activity, although this takes a bit of the fun and personalization out of it.
• It is useful to model each step with the class, especially the frameshift mutations.
• Discussion questions:
• In this model, if your name represents a protein, what do the letters of your name represent?
• What would a change in the amino acid sequence look like on a real protein (how would a real protein be affected)?
• Why is it possible for some mutations to not affect your name?
• Which type of mutation do you think affects a protein’s structure and function more—substitution or insertion? Why?
• How might mutations impact your initial model for explaining genetic variation among family members?

### Resource 15: Modeling Gene Regulation

Simulate the genetic and environmental factors that affect skin color.

Hilleary Osheroff, Exploratorium Teacher Institute

Resource Type
Classroom Activity

Teaching Notes

• This activity provides a concrete example of how a complex trait is controlled by multiple genes, hormones, proteins, and environment, but remember that this simulation is also extremely oversimplified.
• The gene MC1R does not control skin color alone, but it does have a large impact. The effects of various alleles of MC1R on skin color are well-researched, and students’ predictions about what would happen to the system under various mutation scenarios of MC1R can be checked against real studies.
• After this activity, it is important for students to revisit their initial models one more time and revise with new information. The revision in the middle of the unit may be skipped if needed, but this final revisit is critical for you to see any change in understanding.

### Resource 16: Genetics Storyline Sequence

This is the guiding document used to organize this digital teaching box. The structure is based on the Next Generation Science Storylines from Northwestern University.

Daisy Yeung, Exploratorium Teacher Institute

Resource Type
Teaching guide

Teaching Notes

• This resource is meant to show the scope and sequence of the unit. While the resources in this digital teaching box are presented in the same order as those in the storyline, this is only a suggested sequence. The order of activities really should depend on the questions your students want to investigate, to help them create a revised model for the anchoring phenomenon. Each activity or investigation should lead to questions that motivate the next activity or investigation in the sequence.

Science and Engineering Practices

Analyzing and Interpreting Data

• Apply concepts of statistics and probability to scientific and engineering questions and problems, using digital tools when feasible. (HS-LS3-3)

Engaging in Argument from Evidence

• Make and defend a claim based on evidence about the natural world that reflects scientific knowledge, and student-generated evidence. (HS-LS3-2)

Disciplinary Core Ideas

LS1.A Structure and Function

• All cells contain genetic information in the form of DNA molecules. Genes are regions in the DNA that contain the instructions that code for the formation of proteins. (HS-LS3-1)

LS3.A Inheritance of Traits

• Each chromosome consists of a single very long DNA molecule, and each gene on the chromosome is a particular segment of that DNA. The instructions for forming species’ characteristics are carried in DNA. All cells in an organism have the same genetic content, but the genes used (expressed) by the cell may be regulated in different ways. Not all DNA codes for a protein some segments of DNA are involved in regulatory or structural functions, and some have no as-yet known function. (HS-LS3-1)
• In sexual reproduction, chromosomes can sometimes swap sections during the process of meiosis (cell division), thereby creating new genetic combinations and thus more genetic variation. Although DNA replication is tightly regulated and remarkably accurate, errors do occur and result in mutations, which are also a source of genetic variation. Environmental factors can also cause mutations in genes, and viable mutations are inherited. (HS-LS3-2)
• Environmental factors also affect expression of traits, and hence affect the probability of ocurrences of traits in a population. Thus the variation and distribution of traits observed depends on both genetic and environmental factors. (HS-LS3-2, HS-LS3-3)

Crosscutting Concepts

• Empirical evidence is required to differentiate between cause and correlation and make claims about specific causes and effects. (HS-LS3-1, HS-LS3-2)=

Scale, Proportion, and Quantity

• Algebraic thinking is used to examine scientific data and predict the effect of a change in one variable on another. (HS-LS3-3)

Science is a Human Endeavor (Connection to Nature of Science)

• Technological advances have influenced the progress of science and science has influenced advances in technology (HS-LS3-3)
• Science and engineering are influenced by society and society is influenced by science and engineering. (HS-LS3-3)

### More Teaching Boxes

##### Cell Biology Teaching Box

Cells aren’t just the basis of life they’re the basis of biology learning.

##### Homeostasis and the Characteristics of Life Teaching Box

What is life, and how is life maintained?

##### Meiosis and Biological Sex Teaching Box

Let’s talk about sex—the biological concept and the processes that determine it.

## A Special Case: Lethal Alleles

When a genetic defect causes 100% mortality in the offspring it is called a lethal allele. When a lethal allele is present, we don’t “see” any offspring result from the cross (they die before birth) so the proportions in the offspring appear off compared to what we expect from a Punnett square.

Lethal alleles can be dominant or recessive. Recessive lethal alleles cause death in a recessive homozygote (aa). Dominant lethal alleles cause death in a dominant homozygote (AA).

Examples of dominant lethal alleles include Huntington’s disease or achondroplasia (a type of dwarfism). In achondroplasia, individuals with an homozygous dominant genotype die before or shortly after birth. Heterozygotes (Aa) show the dwarf phenotype, and homozygous recessives are of average stature (aa).

Stop and Think: Examine the picture below showing the inheritance of coat color in mice. It shows an example of a dominant lethal allele. What are the genotype and phenotype ratios you would see in the actual mouse population? (answer: P-R is 1 dead, 2 yellow, 1 white )

## Estimation of cases with dominant inheritance - Biology

#### Article Summary:

Gregor Mendel's laws such as Law of Segregation and Law of Independent Assortment describe the basic genetic mechanisms. However, further studies by scientists have showed that the laws need to be expanded to account for more complex patterns of inheritance. Mendel's laws fail to adequately explain some phenomenon like mitochondrial gene inheritance and inheritance due to linkage between genes on the same chromosome and variation in gene expression and gene interactions can produce results other than phenotypic ratio predicted by Mendel's laws. Following are some phenomenons that are not explained by Mendel's laws:

Codominance and Incomplete dominance
Codominance is a phenomenon in which both the different alleles of a heterozygote are fully expressed . Most common example showing co-dominance is the ABO blood group system. A person having "A" allele and "B" allele will have a blood type "AB" because both "A" and "B" alleles are codominant with each other. A heterozygote, in which the dominant allele is only partially expressed, usually in an offspring with an intermediate phenotype, is called incomplete dominance. Technically, incomplete dominance can be termed as lack of dominance. Example for incomplete dominance can be found in Snapdragon plant. Pureline phenotypes of red (RR) and white (rr) give rise to Rr plant with pink flowers. In incomplete dominance the heterozygous plant carrying both alleles Rr will not be able to produce sufficient red pigment. This is because the dominant allele, which is responsible for the production of red pigments, is only partially expressed and therefore the flower has an appearance of pink. Similar situations exist in humans also. A child has higher probability of having a wavy hair if one parent of the child has curly hair and the other straight hair. This is because wavy hair is the intermediate between curly and straight hair.

Penetrance and Expressivity
The terms penetrance and expressivity are used to describe degrees of gene expression. Penetrance is the frequency or rate of a particular trait or condition to occur and is typically expressed as a percentage. Genetic penetrance provides estimation of the likelihood of expression of a particular disease causing gene that will result in disease. If only some individuals actually show the associated traits of a genetic disease while others do not even though they carry the same disease causing genes, then the disease can be said to have incomplete penetrance. Only some individuals with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime but others do not and hence this case can be taken as an example for incomplete penetrance. In the case of every person having a disease causing gene, develops the associated trait or condition, then the disease is said to show hundred percent or complete penetrance. Huntington's disease is an example for complete penetrance. Expressivity refers to the extent of manifestation of the effects by an expressed gene in an organism. In other words, it refers to instances where a phenotype is expressed to a different degree between different individuals but all having same genotype. Marfan disease is an example of this phenomenon. In individuals suffering from Marfan disease, only some have long fingers and toes but others would have a full blown disease with defects of heart valves and aorta.

Pleiotropy
This is a situation where a single gene controls or influences multiple phenotypic traits or the phenotype expresses many symptoms with different subsets in various people. Such conditions are difficult to identify as genetic disorders as individual members of the family may express different subsets of the symptoms which may resemble different disorders altogether. Examples include autosomal dominant disorder- porphyria variegate, in which different combinations of the symptoms in family appear to be different unrelated diseases.

Phenocopy
This the phenomenon in which a phenotype appears to be inherited but is actually caused by environment. Phenocopy can produce symptoms that either resemble a common hereditary disease or occur in certain members of a family there by mimicking inheritance pattern. As an example, frequent colds in an underweight person may match the symptoms of cystic fibrosis but may actually be suffering from malnutrition.

Epistasis
It is a situation in which one gene suppresses or influences the expression of another gene. One of the better known examples of epistasis was reported by Bateson and Punnett in 1905. They crossed two strains of inbred white sweet peas and obtained an F1 progeny that all had purple flowers. Another well know example is Bombay phenotype. It is a result of two interacting genes, "I" and "H".
Although Mendel's laws were basic in nature they initiated the era of genetics. Scientist after Mendel built upon his laws and as a outcome, organised genetics as a branch of science with tremendous commercial and scientific implications.