In eukaryotes, the major mechanism for shuffling genes is sexual reproduction. So what are the benefits of sexual reproduction269?
Sexual reproduction involves the alternation of diploid (two copies of each chromosome) and haploid (one copy of each chromosome) cell types. In a diploid cell, the two copies of a particular gene can be different, the the organisms is said to be heterozygous for that gene. Different alleles can (but do not necessarily do) encode functionally distinct gene products and can be associated with different phenotypes (discussed in greater detail in the future two-semester version). We can then characterize different alleles with respect to one one another. Assume that allele-1 is associated with phenotype-1 and allele-2 is associated with phenotype-2. An organism heterozygous for allele-1 and allele-2 may express one of four phenotypes; it may express phenotype-1, phenotype-2, an new phenotype (phenotype 3), or no distinctive phenotype. If phenotype-1 is found, allele-1 is said to be dominant to allele-2 (which is said to be recessive), if phenotype-2 is found, allele-2 is dominant to allele-1 (which is said to be recessive); if phenotype 3 is found, the two alleles are said to be co-dominant. If both alleles of a gene are the same, the organism is said to be homozygous for that gene. If the phenotype associated with a particular allele is observed only in homozygous individuals, the allele is said to be recessive.
The process of sexual reproduction has two obvious impacts on a population’s genetic variation. The process of homologous recombination, which occurs during the formation of haploid cells, can generate new alleles not present in the original cell. In addition, the generation of haploid cells can reveal the presence of recessive alleles. When the present an isolated recessive allele results in a lethal or highly deleterious phenotype, the haploid cells that contain such an allele will be eliminated, removing the allele from the population.
As we will see below, the process of recombination between homologous chromosome leads to mutations when cells attempt to divide. Avoiding such mutations is thought to be involved in driving the evolution of the linear chromosomes in eukaryotes.Eukaryotes also typically have multiple chromosomes. Each chromosome contains single (linear)double-stranded DNA molecule. Different chromosomes can be distinguished by the genes they contain, as well as the overall length of their DNA molecules. Typically the chromosomes of an organism are numbered from the largest to the smallest. Humans, for example, have 23 pairs of chromosomes. In humans the largest of these chromosomes, chromosome 1, contains ~250 million base pairs of DNA and over 2000 polypeptide-encoding genes, while the smaller chromosome 22 contains ~52 million based pairs of DNA and around 500 polypeptide encoding genes270.
In sexually reproducing organisms, somatic cells are typically diploid, that is, they contain two copies of each chromosome rather than one. The two copies of the same chromosomes are known as homologs of each other or homologous chromosomes. As we will now describe, one of these homologous chromosomes is inherited from the maternal parent and the other from the paternal parent. Two homologous chromosomes are generally similar, with the exception of allelic differences in different genes (also known as genetic position or genetic loci). Theexception to this rule are the so called sex chromosomes. While different types of organisms determine an individual’s sex using differentmechanisms,, in humans (and most mammals, birds and reptiles) the phenotypic sex of an individual is determined by which sex chromosomes their cell’s contain. In humans the 23rd chromosome comes in two forms, known as X and Y. An XX individual typically develops into a female, while an XY individual develops into a male.
When a eukaryotic cell reproduces asexually, it goes through two linked processes known as mitosis (the segregation of chromosomes) and cytokinesis (the generation of two daughter cells). The sexual reproductive cycle involves a modified form of mitosis known as meiosis. It involves two distinct mechanisms not found in mitosis that lead to allele shuffling.
The cells of the body that take an integral part in sexual reproduction (of course, the entire body generally takes part in sex, but we are trying to stay simple here) are known as germ line cells. A germ line cell is diploid but, through the process known as meiosis, produces as many as four haploid cells, known as gametes. The first step in this process is the replication of the cell’s DNA; each individual chromosome is duplicated, that is the DNA molecule it contains are copied to produce two DNA molecules. Instead of separating from one another, these replicated DNA molecules remain attached through associated proteins, at a structure known as the centromere. In standard, asexual (mitotic )division each replicated chromosome interacts independently with a molecular machine, known as the mitotic spindle,that acts to send one copy of each chromosome to each of the two daughter cells. During mitosis a diploid cell produces a diploid cell, and nothing about the genome has changed. The cells that are formed become part of the original organism.
In contrast the purpose of meiosis is to produce a new organism, with a genome distinct from that of either of its parents (even in the case of hermaphrodites, in which one organism acts as both mother and father!) To accomplish this, chromosomes are shuffled in various ways. First, remember that the diploid cell contains two sets of chromosomes, one set from the mother and a set from the father. In meiosis, and in contrast to mitosis,the(now)duplicated homologous (material and paternal)chromosomes form a structure containing of four DNA strands, sometimes called a tetrad. This pairing is based on the fact that the DNA sequences along each homologous chromosome, while not identical, are extremely similar: they are syntenic.271. At this point, at positions more or less random along the length of the chromosome, there are double strand breaks in two of the DNA molecules. The DNA molecules can then be rejoined, either back to themselves (maternal to maternal, paternal to paternal) or with another DNA molecule (maternal to paternal, or paternal to maternal). Typically, multiple “crossing-over” events occur along the length of each set of paired, replicated homologous chromosomes, generally involve different pairs of DNA molecules.
At the first meiotic division, the duplicated maternal and paternal chromosomes remain attached at their centromeres, but if you follow any one DNA molecule from beginning to end you will find that because of crossing over each will, in fact, be different from either the maternal or paternal chromosomes. Each of the two resulting daughter cells will receive either the replicated maternal or paternal chromosome centromere region, but which chromosome (defined by their centromeres, material or paternal) they inherit is a random process. For an organism with 23 different chromosomes, that produces 223 possible different daughter cells. There is no DNA replication before the second meiotic division. During the second meiotic division the two daughter cells each receive a copy of one and only one homologous chromosome (one DNA molecule). The four cells that are generated by meiosis are known as gametes (or at least are potential gametes) and they are haploid..
Let us take a closer look at the chromosomes in these gametes, compared to those in the cells from which they were derived. Our original cell (organism)(on the left of the diagram on the next page) was derived from the fusion of two haploid gametes. These haploid gametes each contained one full set of chromosomes, but those chromosomes differed from one another in the details of their nucleotide sequences, specifically the alleles they contain. There will be nucleotide differences at specific positions (known as single nucleotide polymorphisms or SNPs - pronounced snips) and small insertions and deletions of nucleotide sequences. For our purposes, we will consider only one single chromosome set, but remember there are generally multiple chromosomes (23 pairs in human). In our example, the chromosomes inherited from one parent had alleles P, M, and N, while the chromosome from the other parent had alleles p, m, and n. Barring new mutations (an unrealistic assumption), all of the cells in the body will have the same set of alleles at these genetic positions, and all cells will contain chromosomes similar to the parental PMN and pmn chromosomes (top panel).
Now let us consider what happens when this PMN/pmn organism is about to reproduce (sexually). It will begin meiosis (bottom panel). The processes of homolog pairing and crossing over will generate new combinations of alleles: the four haploid cells illustrated here have pMN, PMn, pmN, and Pmn genotypes. All of these are different from the PMN and pmn parental chromosomes. At fertilization one of these haploid cells will fuse with a haploid cell from another organism, to produce a unique individual. While we have considered only two (or three, if you include the p*, m*, and n* alleles) at three genes, two unrelated individuals will differ from each other by between 3 to 12 million DNA differences. Most phenotypes are influenced to a greater or lesser extent by the entire genotype, new combinations of alleles will generate new phenotypes.
Meiotic recombination arising from crossing over has two other important outcomes. First consider what happens when a new allele arises by mutation on a chromosome. If the allele has a strongly selected, either positive or negative, phenotype, then organisms that inherit that new allele will be selected for (or against). But remember that the allele sits on a chromosome, and is linked to neighboring genes (and their alleles). Without recombination, the entire chromosome would be selected as a unit. In the short term this is still the case, on average, but recombination allows alleles of neighboring genes to disconnect from one another. When the probability of a recombination event between two genes is 50% or greater, the genes appear to behave as if they are on different chromosomes, they become “unlinked.” Linkage distances are calculated in terms of centimorgans, named after the Nobel prize winning geneticist Thomas Hunt Morgan (1866-1945.) A centimorgan corresponds to a 1% chance of a crossing over event between two genes (or specific sites in a chromosome). In humans, a centimorgan corresponds to ~1 million base pairs of DNA, so two genes/alleles/sites along a chromosome separated by more than ~50 million base pairs would be separated by 50 centimorgans and so would appear unlinked. That is, a crossing over event between the two originally linked alleles would be expected to occur 50% of the time, which is the same probability that a gamete would inherit one but not the other allele if the genes were located on different chromosomes.
In addition to shuffling alleles, meiotic crossing over (recombination) can create new alleles. Consider the situation in which the two alleles of a particular gene in a diploid organism are different from one another. Let us assume that each allele contains a distinct sequence difference (as marked). If, during meiosis, a crossing over event takes place between these sites, it can result in an allele that contains both molecular sequences (AB), and one with neither (indicated as WT), in addition to the original A and B allele chromosomes.