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Dig deep: Is genetic recombination linked to the expression of harmful traits?

Most mammals, including humans, are diploid. That is, nuclear DNA (nrDNA) exists as a pair of chromosomes (humans have 23 pairs of chromosomes, while mice have 20). This chromosome pair is homologous because the gene sequence on both chromosomes is the same. However, a gene located at a specific address (‘locus’) may have different ‘alleles’ on the homologous chromosomes. For the sake of understanding, if we were to assume that the height is determined by a particular gene that sits on, say, the 6th chromosome, one of the chromosomes could carry a genetic sequence for short height – rather “allele” for shortness – and the other can carry the gene for longevity. (In reality, no gene is responsible for height and it is a trait that is determined by a combination of genes, not least the environment and nutrition). In this pretend example above, if both chromosomes in the pair were to carry the allele for shortness, we would say that the individual, or sequence, is homozygous for shortness at that point, or heterozygous if both chromosomes were to carry different alleles. The same logic applies when we consider species where the genetic code is found in triplets and not pairs, a condition called triploid.

This determines the genotype of an individual for the specific trait / gene / locus. For example, for a flower species that may have white and yellow flowers, the genotype of a particular flower may be YY (alleles for a yellow flower on both chromosomes) or WY or YW (an allele on both) or WW (white allele on both). If W was the recessive allele and Y the dominant one, a heterozygous flower will have a yellow phenotype.

A harmful allele puts the individual at a disadvantage in some way. A harmful allele may well be the dominant one. But in that case, it will reduce the individual’s fitness and the genotype will have less chance of being passed on to the next generation.

However, things get complicated when the same genotype results in different phenotypes – a phenomenon called allele-specific expression (ASE). A study published this week by a team of researchers from Canada highlights this. They find that regions of the genome that are likely to undergo recombination are also more likely to flush out a set of harmful alleles.

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Recombination is a phenomenon where chromosomes in a pair are broken up, their codes recombined to produce a new sequence of alleles. It is characteristic of meiosis, a type of cell division that occurs when germ cells (sperm or eggs) are formed. The resulting sequence in sperm / egg is monoploid, which means that it does not exist as a pair. The pair is formed only when the sperm and the egg fuse. A set of alleles / traits that are transmitted from one generation to another is called a “haplotype”.

There are regions in the genome that show a greater affinity for recombination (recombination hotspots) and then there are regions that show a smaller affinity for the same (coldspots). The latter, of course, allows harmful mutations to accumulate and reach what we call “fixation”. Harwood et al (2022) classify recombination regions as low (ie coldspot, CS), normal and high recombination (HRR). The study genotyped almost 1596 individuals and measured their allele expression. These 1596 individuals consisted of 844 individuals from Quebec, Canada, as part of the CARTaGENE project and 752 from the Genotype Tissue Expression project. It was found that “enrichment of ASE in HRR / normal regions was observed in all tissues examined.”

Take advantage of the Genotype Tissue Expression Project (GTEx), a previous study 2018 had established that, in a general population, purifying selection depletes the haplotypes in which harmful mutations have accumulated and is likely to have an “increased pathogenic penetration.” They had also found it cancer patients, enrich the penetration of these harmful haplotype configurations. To expand this finding, Harwood et al (2022) observed that in regions with high or normal recombination, potentially pathogenic alleles are underexpressed and overexpressed in recombination cold spots.

It is important to note historical context in Quebec, Canada also. The population was inhabited by French colonizers 400 years ago, along with smaller colonies such as the Saguenay-Lac-Saint-Jean region. It is also well known that when the population size is small, there is a greater chance of non-random associations between alleles from different loci, due to a reduced gene pool. Natural selection has little genetic diversity left to work with in that case – and it is done quite inefficiently. Therefore, the Saguenay region shows a high level of kinship, compared to African or European populations that have more efficient natural selection processes acting on them. “The signature of African individuals with increased odds of ASE in HRR / Normal compared to CS was also shown in GTEx muscle, brain, ovarian, lung and liver tissue,” the study claims.

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Environmental history also plays a key role, the study finds. While examining genes that had provided expression data across regions and environments. They observed that individuals with ancestry in Saguenay but currently living in different regions such as Montreal, Quebec City and Saguenay had “differential allele-specific expressions”.

The study is an important step in understanding a long-standing issue in evolutionary biology: how past demographic changes, population sizes and genetic drift interact with recombination and affect gene expression. The study highlights its implications for predicting disease risks in populations and states that “gene expression is an important step in translating genotypes into phenotypes, and understanding how gene expression is regulated and developed is crucial to deconvolving the relationship between phenotypic variation and disease penetration across human populations. . ‘

The author is a researcher at the Indian Institute of Science (IISc), Bengaluru, and a freelance science communicator. He tweets at @critvik.

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