Weakening of Y promoters shaped the evolution of human sex chromosomes
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harris-hlharris-phd-biology-2024-thesis .pdf
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Author(s)
Harris, Hannah Lily
Advisor(s)
Page, David C.
Date Issued
September 2024
Publisher
Massachusetts Institute of Technology
Abstract
The presence of two sex chromosomes is vital for life. Each individual’s body contains an active X chromosome and either an inactive X or a Y chromosome. This represents the source of the largest genetic variation among any two humans. Understanding the similarities and differences generated from having an Xi or a Y is essential for studies of sex differences. A subset of the genes expressed from the X chromosome have homologs that reside on the Y chromosome. These genes, termed X-Y homologs or X-Y pairs, have been evolving for millions of years in the absence of crossing over between the sex chromosomes. They are expressed widely throughout the body, dosage sensitive, and critical in a number of essential biological functions. The presence of X-Y pairs explains why humans cannot survive without a second sex chromosome in at least a proportion of their cells: the appropriate dosage of X-Y pair genes is essential.
Although the Y homologs are under strong purifying selection, they are often expressed at lower levels than their X counterparts. This observation runs counter to our expectation that these genes remain on Chr Y because maintaining the ancestral gene dosage is important. In an effort to understand this observation, we asked how X-Y pair promoters have evolved. We found that X-Y pair promoters are highly diverged, driven by a decrease in G+C content of the Y-linked promoters. These Y-linked promoters evolved very rapidly due to the fast male germline mutation rate and are under less constraint than their X counterparts. In a massively parallel reporter assay (MPRA), we find that sequence changes, particularly loss of G+C content, have weakened Y promoters as compared to their X counterparts. These results add to our model of sex chromosome evolution: As Y promoters weakened and Y pair genes lost expression, the X chromosome was forced to upregulate expression on the active X and subsequently reduce expression of X homologs from the inactive X. This model resolves observed expression level differences while meeting the expectation put forth by previous models that maintenance of ancestral gene dosage is critical. Our findings highlight a prominent role for regulatory sequences in X-Y homolog evolution.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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