CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it>
<p>Abstract</p> <p>Background</p> <p>Elucidating the pattern of evolutionary changes in drug-metabolizing genes is an important subject not only for evolutionary but for biomedical research. We investigated the pattern of divergence and polymorphisms of macaque <it&g...
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doaj-4e71b9bcba9344558a61b368ee0153232021-09-02T05:50:44ZengBMCBMC Evolutionary Biology1471-21482011-10-0111128310.1186/1471-2148-11-283CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it>Osada NaokiUno Yasuhiro<p>Abstract</p> <p>Background</p> <p>Elucidating the pattern of evolutionary changes in drug-metabolizing genes is an important subject not only for evolutionary but for biomedical research. We investigated the pattern of divergence and polymorphisms of macaque <it>CYP1A1 </it>and <it>CYP1A2 </it>genes, which are major drug-metabolizing genes in humans. In humans, <it>CYP1A2 </it>is specifically expressed in livers while <it>CYP1A1 </it>has a wider gene expression pattern in extrahepatic tissues. In contrast, macaque <it>CYP1A2 </it>is expressed at a much lower level than <it>CYP1A1 </it>in livers. Interestingly, a previous study has shown that <it>Macaca fascicularis CYP1A2 </it>harbored unusually high genetic diversity within species. Genomic regions showing high genetic diversity within species is occasionally interpreted as a result of balancing selection, where natural selection maintains highly diverged alleles with different functions. Nevertheless many other forces could create such signatures.</p> <p>Results</p> <p>We found that the <it>CYP1A1/2 </it>gene copy number and orientation has been highly conserved among mammalian genomes. The signature of gene conversion between <it>CYP1A1 </it>and <it>CYP1A2 </it>was detected, but the last gene conversion event in the simian primate lineage occurred before the <it>Catarrhini-Platyrrhini </it>divergence. The high genetic diversity of macaque <it>CYP1A2 </it>therefore cannot be explained by gene conversion between <it>CYP1A1 </it>and <it>CYP1A2</it>. By surveying <it>CYP1A2 </it>polymorphisms in total 91 <it>M. fascicularis </it>and <it>M. mulatta</it>, we found several null alleles segregating in these species, indicating functional constraint on <it>CYP1A2 </it>in macaques may have weakened after the divergence between humans and macaques. We propose that the high genetic diversity in macaque <it>CYP1A2 </it>is partly due to the degeneration of CpG sites, which had been maintained at a high level by purifying selection, and the rapid degeneration process was initiated by the loss of functional constraint on macaque <it>CYP1A2</it>.</p> <p>Conclusions</p> <p>Our findings show that the highly polymorphic <it>CYP1A2 </it>gene in macaques has not been created by balancing selection but by the burst of CpG site degeneration after loss of functional constraint. Because the functional importance of <it>CYP1A1/2 </it>genes is different between humans and macaques, we have to be cautious in extrapolating a drug-testing data using substrates metabolized by <it>CYP1A </it>genes from macaques to humans, despite of their somewhat overlapping substrate specificity.</p> http://www.biomedcentral.com/1471-2148/11/283 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Osada Naoki Uno Yasuhiro |
spellingShingle |
Osada Naoki Uno Yasuhiro CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it> BMC Evolutionary Biology |
author_facet |
Osada Naoki Uno Yasuhiro |
author_sort |
Osada Naoki |
title |
CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it> |
title_short |
CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it> |
title_full |
CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it> |
title_fullStr |
CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it> |
title_full_unstemmed |
CpG site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>CYP1A2</it> |
title_sort |
cpg site degeneration triggered by the loss of functional constraint created a highly polymorphic macaque drug-metabolizing gene, <it>cyp1a2</it> |
publisher |
BMC |
series |
BMC Evolutionary Biology |
issn |
1471-2148 |
publishDate |
2011-10-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Elucidating the pattern of evolutionary changes in drug-metabolizing genes is an important subject not only for evolutionary but for biomedical research. We investigated the pattern of divergence and polymorphisms of macaque <it>CYP1A1 </it>and <it>CYP1A2 </it>genes, which are major drug-metabolizing genes in humans. In humans, <it>CYP1A2 </it>is specifically expressed in livers while <it>CYP1A1 </it>has a wider gene expression pattern in extrahepatic tissues. In contrast, macaque <it>CYP1A2 </it>is expressed at a much lower level than <it>CYP1A1 </it>in livers. Interestingly, a previous study has shown that <it>Macaca fascicularis CYP1A2 </it>harbored unusually high genetic diversity within species. Genomic regions showing high genetic diversity within species is occasionally interpreted as a result of balancing selection, where natural selection maintains highly diverged alleles with different functions. Nevertheless many other forces could create such signatures.</p> <p>Results</p> <p>We found that the <it>CYP1A1/2 </it>gene copy number and orientation has been highly conserved among mammalian genomes. The signature of gene conversion between <it>CYP1A1 </it>and <it>CYP1A2 </it>was detected, but the last gene conversion event in the simian primate lineage occurred before the <it>Catarrhini-Platyrrhini </it>divergence. The high genetic diversity of macaque <it>CYP1A2 </it>therefore cannot be explained by gene conversion between <it>CYP1A1 </it>and <it>CYP1A2</it>. By surveying <it>CYP1A2 </it>polymorphisms in total 91 <it>M. fascicularis </it>and <it>M. mulatta</it>, we found several null alleles segregating in these species, indicating functional constraint on <it>CYP1A2 </it>in macaques may have weakened after the divergence between humans and macaques. We propose that the high genetic diversity in macaque <it>CYP1A2 </it>is partly due to the degeneration of CpG sites, which had been maintained at a high level by purifying selection, and the rapid degeneration process was initiated by the loss of functional constraint on macaque <it>CYP1A2</it>.</p> <p>Conclusions</p> <p>Our findings show that the highly polymorphic <it>CYP1A2 </it>gene in macaques has not been created by balancing selection but by the burst of CpG site degeneration after loss of functional constraint. Because the functional importance of <it>CYP1A1/2 </it>genes is different between humans and macaques, we have to be cautious in extrapolating a drug-testing data using substrates metabolized by <it>CYP1A </it>genes from macaques to humans, despite of their somewhat overlapping substrate specificity.</p> |
url |
http://www.biomedcentral.com/1471-2148/11/283 |
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