Roxana Daneshjou
medical student
Stanford University

Tao, AK, CN

What is the relationship between mutation and recombination (in meiosis)? Does the frequency of recombination correlate with mutation rate? Do recombination and mutation work together to promote human evolution?

Roxana Daneshjou
HHMI medical fellow,
medical student,
School of Medicine,
Stanford University

Let’s start with a basic overview of these two processes.

A mutation is a change in the genome, which can be advantageous, deleterious, or neutral. When discussing meiosis, we are specifically talking about germline de novo mutations—mutations in the gametes, which can be passed on to the next generation (as opposed to somatic mutations, which are mutations that happen in nongamete cells in the body and are not passed on). These changes can occur at many levels. For example, the mutation can be a change in a single nucleotide or an insertion/deletion of many nucleotides (to name just a few possibilities) (1).

Recombination is a required part of meiosis that occurs during prophase I. During recombination, the crossing over of genetic material between homologous chromosomes produces daughter cells with a different allelic composition from that of the parent cells (2).

Both processes are mechanisms of generating genetic diversity. However, mutations are “errors”; that is, meiosis does not aim to produce germline mutations, and the process is thought to be random. These errors can end up being neutral, beneficial, or detrimental for the organism. Recombination, on the other hand, is a process that is built in to the meiotic machinery and is actually required to complete meiosis. Mutations can occur as a result of recombination gone wrong—mis-segregation of chromosomes can lead to aneuploid gametes (in which the daughter cells have missing or extra chromosomes). Aneuploidies are a leading cause of birth defects and miscarriages (1, 2).

How do these two processes affect evolution? Well, there is some fascinating research surrounding that question.

Let’s start with germline mutations. One of the first things one has to wonder is how often germline mutations occur (i.e., new mutations that are passed on to the daughter cell but are not carried by the somatic cells of the parent). In the past, two methods have been used to study this question: looking at multiple generations and the number of mutations that have occurred and looking across species and inferring mutations based on genetic variability. According to these estimates, base substitution rates range from 1.1 to 3 × 10–8 per generation. With 6 billion bases, that means that somewhere between 66 and 180 changes occur between parent and offspring due to germline mutations! And even more interestingly, a recent study in Nature Genetics has suggested that the de novo germline mutation rates in the gametes may not only be lower than those previously reported numbers but also may be highly variable between paternal and maternal lines (in one case, the paternal line was more responsible, in another the maternal) (1). Research like this has made it clear that we have a lot more to learn. As for how all of this affects evolution, research is still under way to answer that question as well. As mentioned before, de novo germline mutations can certainly lead to disease (not evolutionarily beneficial), and a recent exome study identified de novo germline mutations in brain development genes to be responsible for some cases of autism (3). Studies in other organisms have shown that de novo mutations are important for survival—a population of yeast limited to a glucose environment will evolve so that the cells that successfully proliferate are those with mutations that allow them to survive in this environment (e.g., mutations that allow increased uptake and more efficient use of glucose). But, in some cases, the same mutations can cause problems—the same yeast that have mutated to have increased usage of glucose cannot survive as well in glucose-rich environments (4). We see trade-offs in human mutations that are thought to increase fitness. Malaria is a devastating parasitic disease prevalent in certain parts of the world, such as Africa. At some point, a de novo germline mutation occurred that conferred a level of protection against the disease. This mutation in hemoglobin is carried at high frequency in the same regions of the world where malaria is prevalent. But while being a heterozygous carrier of this trait is protective against malaria, having two copies of the mutation leads to a devastating disease—sickle cell anemia, in which the abnormally sickle-shaped blood cells detrimentally affect blood flow and tissue oxygenation, leading to increased rates of tissue damage and infection (5). We can see from all this that humans and mutations have a very complex relationship. In some cases, mutations are quite detrimental, but in others, they confer advantages that allow a population to better survive under particular conditions.

As stated before, recombination is the regulated exchange of genetic material during meiosis, which creates daughter cells with allelic compositions distinct from the parent cells. Recombination theory in population genetics states that recombination helps advance evolution. The reason is this: imagine a population acquires two advantageous but different mutations, producing mutant x and mutant y. If mutant x and mutant y can mate and recombine, then a new mutant can be produced—mutant xy—that has both advantageous mutations. However, if they cannot recombine, mutant xy will arise only when a member of x or y randomly acquires the other’s beneficial mutation by chance. Another evolutionary advantage of recombination is something referred to as “Muller’s rachet”—the idea that recombination allows a population to purge deleterious changes while a lack of recombination allows the accumulation of deleterious mutations in a population. Imagine an organism that cannot undergo recombination; as different members accumulate deleterious mutations, nothing can be done to purge those mutations during the process of reproduction. However, through recombination, genetic material is exchanged, and the possibility exists that all the deleterious mutations end up on one chromosome, while the other chromosome is devoid of any deleterious mutations. The genetic material with the least amount of deleterious mutations can then be selected for through natural selection (6). In one study, scientists compared genomic regions with and without recombination in fruit flies. This study claimed to detect both processes: a degeneration in regions without recombination due to a persistence of deleterious effects and an accumulation of beneficial alleles in areas with recombination (7, 8). Now, some more recent findings on recombination provide additional food for thought.

The number of recombination events per meiosis varies among individuals. However, recombination is definitely a feature of the genome—with hotspots occurring about every 200 kilobases (9). Additional studies have been trying to identify regions of the genome associated with recombination rates. This means that genetic variants in genomes could influence how much recombination occurs. If this is true, then any mutation that arises in one of these regions could ultimately influence recombination—yet another link between these two processes (10).

Mutation and recombination both produce genetic diversity, but they are quite different processes. We still have a lot to learn on both fronts, but research is continually shedding light on how these processes influence adaptation and evolution.

References:
1. Conrad, D.F., et al. 2011. Variation in genome-wide mutation rates within and between human families. Nature Genetics 43(7): 712–4.
2. Brachet, E., et al. 2012. Interplay between modifications of chromatin and meiotic recombination hotspots. Biology of the Cell 104(2): 51–69.
3. Sanders, S.J., et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature.
4. Wenger, J.W., et al. 2011. Hunger artists: yeast adapted to carbon limitation show trade-offs under carbon sufficiency. PLoS Genetics 7(8): e1002202.
5. Allison, A.C. 1954. Protection afforded by sickle-cell trait against subtertian malareal infection. British Medical Journal 1(4857): 290–4.
6. Felsenstein, J. 1974. The evolutionary advantage of recombination. Genetics 78(2): 737–56.
7. Carvalho, A.B. 2003. The advantages of recombination. Nature Genetics 34(2): 128–9.
8. Bachtrog, D. Adaptation shapes patterns of genome evolution on sexual and asexual chromosomes in Drosophila. Nature Genetics 34(2): 215–9.
9. McVean, G.A.T., et al. 2004. The fine-scale structure of recombination rate variation in the human genome. Science 304(5670): 581–4.
10. Chowdhury, R., et al. 2009. Genetic analysis of variation in human meiotic recombination. PLoS Genetics 5(9): e1000648.

03/11/12 18:31