Most mammals, including humans, are diploid. That is, nuclear DNA (nrDNA) exists as pairs of chromosomes (humans have 23 pairs of chromosomes, while mice have 20). This pair of chromosomes is homologous, with the sequence of genes on both chromosomes being the same. However, a gene that sits at a particular address (‘locus’) may have different ‘alleles’ on its homologous chromosomes. To illustrate, if we assume that height is determined by a particular gene, say, the 6th chromosome, one of the chromosomes may carry the genetic sequence for short height – rather, the ‘allele’ for shortness. – and the other can carry genes for length. (In fact, there is no single gene responsible for height and it is determined by a combination of genes, not least environment and nutrition). In this make-belief 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 locus, or heterozygous if both chromosomes had different alleles. to take away. The same logic applies when we consider species where the genetic code exists in triplets and not in pairs, a condition known as triploidy.
It determines the genotype of an individual for that particular trait/gene/locus. For example, for a flower species that may have white and yellow flowers, the genotype of a particular flower is YY (the allele for the yellow flower on both chromosomes) or WY or YW (either one allele) or WW (white on both). alleles) may occur. , If W is the recessive allele, and Y is the dominant one, a heterozygous flower will have a yellow phenotype.
A deleterious allele puts the individual at a disadvantage in some way or the other. A deleterious allele can be very dominant. But, in that case, it is going to reduce the fitness of the individual and the genotype is going to be less likely to be passed on to the next generation.
However, matters become 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 that. They find that regions of the genome where recombination is likely to occur are also more likely to carry out a set of deleterious alleles.
recombination is a phenomenon in which chromosomes in a pair break off, their codes recombine to produce a new sequence of pairs. It is characterized by meiosis, a type of cell division that occurs when gamete cells (sperm or ova) are forming. In spermatozoa/ova the resulting sequence is monoploid which means it does not exist as a pair. Pairing occurs only when sperm and egg unite. A set of alleles/traits that are passed from one generation to another is known as a ‘haplotype’.
There are regions of the genome that exhibit greater affinity for recombination (recombination hotspots) and then there are regions that exhibit lower affinity for the same (coldspots). The latter naturally allows deleterious mutations to accumulate and access what we call ‘fixation’. Harwood et al (2022) classify the recombination regions as low (ie coldspot, CS), normal and high recombination (HRR). The study genotyped approximately 1596 individuals and measured their allele expression. These 1596 individuals included 844 individuals from Quebec, Canada as part of the CartaGen project and 752 individuals from the Genotype Tissue Expression Project. It was found that ‘enrichment of ASE in HRR/common areas was observed in all the tissues examined.’
Capitalizing on the Genotype Tissue Expression Project (GTEx), A previous study in 2018 established that, in a general population, purifying selection reduces haplotypes where deleterious mutations have accumulated and will likely lead to ‘increased pathogen infiltration’. He also found that cancer patients, the penetrance of these deleterious haplotype configurations is enriched. Extending this finding, Harwood et al (2022) observed that in regions of high or normal recombination, potentially disease-causing alleles are underexpressed, and overexpressed in recombination coldspots.
it is important to note Historical context of Quebec, Canada Too. 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 well known that when the population size is small, there is a greater likelihood of non-random associations between alleles at different loci due to the reduced gene pool. There is too little genetic diversity left for natural selection to work in that case – and it is quite inefficient. Therefore, the Saguenay region shows a higher level of relatedness than African or European populations, which have more efficient natural selection processes. ‘The signature GTEX of African individuals with increased odds of HRR/ASE in normal compared to CS was also demonstrated in muscle, brain, ovarian, lung and liver tissue,’ the study argues.
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The study found that environmental histories also play an important role. When examining genes that had expression data across regions and environments was obtained. They observed that individuals with ancestry in Saguenay but living in different areas such as present-day Montreal, Quebec City and Saguenay had ‘differential allele-specific expression’.
The study is an important step forward in understanding a long-standing question in evolutionary biology: how past demographic changes, population size and genetic drift interact with recombination and affect gene expression. Highlighting its implications in predicting disease risks in populations, the study states that ‘gene expression is an important intermediate step in translating genotype into phenotype, and thus understanding how gene expression is regulated and evolved. It is important to delineate the relationship between phenotypic variation and disease penetrance. in human population.’
The author is a Research Fellow at the Indian Institute of Science (IISc), Bengaluru and is a freelance science communicator. he tweeted @critic.