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Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

ABSTRACT: Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

PROVIDER: PRJNA720645 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14183943_1.fastq.gz	Fastqsanger.gz
	SRR14183943_2.fastq.gz	Fastqsanger.gz
	SRR14183944_1.fastq.gz	Fastqsanger.gz
	SRR14183944_2.fastq.gz	Fastqsanger.gz
	SRR14183945_1.fastq.gz	Fastqsanger.gz

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Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor

Project description:The deletion of the third exon of the growth hormone receptor (GHR) is one of the most common genomic structural variants in the human genome. This deletion (GHRd3) has been linked to response to growth hormone, placenta size, birth weight, growth after birth, time of puberty, adult height, and longevity. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. Here, we analyzed thousands of genomes and provide evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals. However, it underwent a paradoxical adaptive reduction in frequency approximately 30 thousand years ago in East Asia that roughly corresponds with the emergence of archaeological evidence for multiple modern human behaviors, dramatic changes in climate, and a concurrent population expansion. Further, we provide evidence that GHRd3 is associated with protection from edematous severe acute malnutrition primarily in males. Using a mouse line engineered to contain the deletion, we found Ghrd3's effect on the liver transcriptome of male mice grown without any calorie restriction mimics response to calorie restriction through regulation of circadian pathways. In contrast, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers. As a likely consequence, the dramatic weight difference between male and female mice disappears among GHRd3 mice under calorie restriction. Our data provide evidence for sex- and environment-dependent effects of GHRd3 and are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability.

2021-04-30 | GSE171716 | GEO

Sex-specific phenotypic effects and evolutionary history of an ancient polymorphic deletion of the human growth hormone receptor.

Project description:The common deletion of the third exon of the growth hormone receptor gene (GHRd3) in humans is associated with birth weight, growth after birth, and time of puberty. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. We present evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals but underwent a recent adaptive reduction in frequency in East Asia. We documented that GHRd3 is associated with protection from severe malnutrition. Using a novel mouse model, we found that, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers and the disappearance of sexual dimorphism in weight. The sex- and diet-dependent effects of GHRd3 in our mouse model are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability.

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Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy

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