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Ohnologs in the human genome are dosage balanced and frequently associated with disease



Institution: National Academy of Sciences
Subject Keywords: Genetics; whole genome duplication; copy number variation; Down Syndrome; trisomy 21;

About 30% of protein-coding genes in the human genome are
related through two whole genome duplication (WGD) events.
Although WGD is often credited with great evolutionary importance,
the processes governing the retention of these genes and
their biological significance remain unclear. One increasingly popular
hypothesis is that dosage balance constraints are a major
determinant of duplicate gene retention. We test this hypothesis
and show that WGD-duplicated genes (ohnologs) have rarely
experienced subsequent small-scale duplication (SSD) and are also
refractory to copy number variation (CNV) in human populations
and are thus likely to be sensitive to relative quantities (i.e., they are
dosage-balanced). By contrast, genes that have experienced SSD
in the vertebrate lineage are more likely to also display CNV. This
supports the hypothesis of biased retention of dosage-balanced
genes after WGD. We also show that ohnologs have a strong
association with human disease. In particular, Down Syndrome (DS)
caused by trisomy 21 is widely assumed to be caused by dosage
effects, and 75% of previously reported candidate genes for this
syndrome are ohnologs that experienced no other copy number
changes. We propose the remaining dosage-balanced ohnologs on
chromosome 21 as candidate DS genes. These observations clearly
show a persistent resistance to dose changes in genes duplicated by
WGD. Dosage balance constraints simultaneously explain duplicate
gene retention and essentiality after WGD

Suggested citation:

MC LYSAGHT, AOIFE; . () Ohnologs in the human genome are dosage balanced and frequently associated with disease [Online]. Available from: [Accessed: 20th October 2019].


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