Deep digging: is genetic recombination linked to expression of deleterious traits?

Most mammals, including humans, are diploid. That is, DNA exists as pairs of chromosomes (humans have 23 pairs of chromosomes, while mice have 20 pairs). This pair of chromosomes is homologous, since the sequence of genes on both chromosomes is the same. However, a gene located on a particular label (“locus”) can have different “alleles” on homologous chromosomes. For the sake of understanding, if we assume that height is determined by a particular gene sitting, let’s say, on chromosome VI, one chromosome could carry the gene sequence for short height – alternatively, an “allele” for short – and the other could carry the tall gene. (In fact, no single gene is responsible for height and it is a trait determined by a group of genes, not least of which is environment and nutrition.) In this dummy example above, if both chromosomes in the pair would carry the allele for shortness, we would say that the individual, or sequence, is homozygous for shorts at that locus, or heterozygous if both chromosomes were to carry the different alleles. The same reasoning applies even when we look at species in which the genetic code is found in triplets rather than pairs, a condition known as triploidy.

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

The harmful allele puts the individual at a disadvantage in some way. The deleterious allele can be largely dominant. But, in this case, it will reduce the fitness of the individual and the chance of transmitting the genotype to the next generation will decrease.

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 Canadian researchers sheds light on this. They found that regions of the genome that are likely to undergo recombination are also more likely to eliminate a group of deleterious alleles.

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Reassemble It is a phenomenon by which chromosomes break apart in a pair, and their codons recombine to produce a new sequence of alleles. It is characteristic of meiosis, a type of cell division that occurs when gamete cells (sperm or eggs) are formed. The resulting sequence in the sperm/ova is haploid which means that it does not exist as a pair. A pair is formed only when the sperm and egg fuse. The set of alleles/traits that are passed down from one generation to another is known as the ‘haplotype’.

There are regions of the genome that show greater affinity for recombination (recombination hotspots) and then there are regions that show less affinity for themselves (cold spots). The latter naturally allows harmful mutations to accumulate and reach what we call “fixation”. Harwood et al (2022) classify areas of low recombination (ie, cold point, CS), normal and high recombination (HRR). The study identified a genotype of approximately 1,596 individuals and measured the expression of their allele. These 1,596 individuals consisted of 844 individuals from Quebec, Canada, as part of the CARTaGENE project and 752 individuals from the Genotype Tissue Expression project. found that “ASE enrichment in HRR/normal regions was observed in all tissues examined.”

Taking advantage of the Gene Tissue Expression (GTEx) project, Previous study in 2018 demonstrated that, in the general population, purification of selection depletes those haplotypes in which deleterious mutations have accumulated and are more likely to have ‘increased pathogenic penetration’. They also found that in cancer Patients, the penetration of harmful haplotype formations is enriched. To extend this finding, Harwood et al (2022) note that in regions of high or normal recombination, alleles likely to cause disease are less expressed, and overexpressed in cold spots of recombination.

Important to note Historical context of Quebec, Canada like that. The population was settled by French colonists 400 years ago, along with smaller colonies such as the Saguenay-Lac-Saint-Jean region. It is also known that when the community size is small, there are greater chances of non-random associations between alleles from different loci, due to the lower gene pool. Natural selection has very little genetic diversity left to work with in this case – and it becomes completely ineffective. Therefore, the Saguenay region shows a high level of relatedness, compared to African or European populations that have more efficient natural selection processes operating on them. The study argues that “the signature of African individuals with increased odds of ASE in HRR/Normal compared to CS also appeared in GTEx tissues in muscle, brain, ovary, lung and liver.”

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The study found that environmental histories play a major role, too. While examining genes yielded expression data across regions and environments. They note that individuals with ancestry in Saguenay but currently residing in different regions such as Montreal, Quebec City and Saguenay, have ‘differential allele-specific expression’.

The study is an important step in understanding a longstanding question in evolutionary biology: how past demographic changes, population sizes, and genetic drift interact with recombination and influence gene expression. Highlighting its implications for predicting disease risk in populations, the study says that “gene expression is a key intermediate step in translating genotypes into phenotypes, and thus understanding how gene expression is regulated and evolved is critical to decoupling phenotypic variance and penetrance. disease through humans.

The author is a Research Fellow at the Indian Institute of Science (IISc), Bengaluru, and an independent science panellist. tweets in Tweet embed

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