Angela
Elite member
- Messages
- 21,823
- Reaction score
- 12,329
- Points
- 113
- Ethnic group
- Italian
See:
http://www.cell.com/fulltext/S0092-8674(17)30128-9
Rajiv C. McCoy et al:
[h=1]Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression[/h]
"
[h=2]Summary[/h]Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes."
" Furthermore, a recent analysis of electronic medical records presented evidence that Neanderthal alleles are associated with a range of clinical traits, including depression, actinic keratosis, hypercoagulation, and tobacco use (Simonti et al., 2016)"
"This example thus adds to growing evidence that Neanderthal introgression contributed to risk of autoimmune disorders (Sankararaman et al., 2014) and innate immune response (Quach et al., 2016, Nédélec et al., 2016)."
" Brain regions had significantly lower expression of Neanderthal alleles (binomial GLMM: β = −0.0168, 95% CI [−0.0200, −0.0136], p < 10−10) than non-brain tissues, particularly in the neuron-rich cerebellum (BRNCHA) and basal ganglia regions (BRNCDT, BRNPTM, BRNNCC)."
"Our analysis revealed that downregulation of Neanderthal alleles was especially pronounced in the cerebellum and basal ganglia (Figure 5A). These brain regions have traditionally been associated with motor control and perception, but a broader role in cognitive function—including language processing—and behavior is now appreciated (Booth et al., 2007, Mariën et al., 2014). Intriguingly, the cerebellum has undergone rapid expansion in the great ape lineage (Barton and Venditti, 2014), and modern humans possess proportionally larger cerebella (greater cerebellum to total brain volume ratio) than did Neanderthals (Hublin et al., 2015)."
"Mutations and polymorphisms in this gene have been associated with a range of neuropsychiatric and neurological disorders including depression (Juhasz et al., 2011), suicide attempts (Murphy et al., 2011, Kohli et al., 2010), impaired speech and language development (Yeo et al., 2004), severe obesity (Gray et al., 2007), autism (Correia et al., 2010), obsessive-compulsive disorder (Alonso et al., 2008), Alzheimer’s disease (Chen et al., 2008), anorexia nervosa (Ribases et al., 2005), nicotine dependence (Li et al., 2008, Beuten et al., 2007), and pilocytic astrocytoma (Jones et al., 2013). Intriguingly, NTRK2 is among a small set of brain-specific genes whose regulatory domains overlap signatures of modern human selective sweeps that occurred after divergence from Neanderthals (Peyrégne et al., 2016)."
"Testis-expressed genes exemplifying the broader pattern of downregulation of Neanderthal alleles include DNALI1 (rs41267319, binomial GLMM: β = −0.476, 95% CI [−0.519, −0.432], p < 10−10, MAFEUR = 0.055), which encodes an axonemal dynein protein that functions in the sperm flagella. Highlighting the potential fitness consequences of introgression on testis-expressed genes, altered regulation of this gene set has been shown to contribute to hybrid incompatibility in other species (Turner and Harr, 2014). Consistent with this observation, genes with high expression in the testes are significantly depleted of Neanderthal ancestry, suggesting that purifying selection disproportionately removed Neanderthal haplotypes at these genes following introgression (Sankararaman et al., 2014). This finding is also consistent with the hypothesis that male hybrid individuals may have incurred reduced fertility (Sankararaman et al., 2014, Sankararaman et al., 2016, Currat and Excoffier, 2011)."
http://www.cell.com/fulltext/S0092-8674(17)30128-9
Rajiv C. McCoy et al:
[h=1]Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression[/h]
"
- •We devised a flexible method to quantify allele-specific expression across samples
- •One-quarter of Neanderthal-introgressed haplotypes show cis-regulatory effects
- •Introgressed regulatory variants add to genomic complexity and phenotypic diversity
- •Neanderthal alleles are downregulated in genes expressed in the brain and testes
[h=2]Summary[/h]Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes."
" Furthermore, a recent analysis of electronic medical records presented evidence that Neanderthal alleles are associated with a range of clinical traits, including depression, actinic keratosis, hypercoagulation, and tobacco use (Simonti et al., 2016)"
"This example thus adds to growing evidence that Neanderthal introgression contributed to risk of autoimmune disorders (Sankararaman et al., 2014) and innate immune response (Quach et al., 2016, Nédélec et al., 2016)."
" Brain regions had significantly lower expression of Neanderthal alleles (binomial GLMM: β = −0.0168, 95% CI [−0.0200, −0.0136], p < 10−10) than non-brain tissues, particularly in the neuron-rich cerebellum (BRNCHA) and basal ganglia regions (BRNCDT, BRNPTM, BRNNCC)."
"Our analysis revealed that downregulation of Neanderthal alleles was especially pronounced in the cerebellum and basal ganglia (Figure 5A). These brain regions have traditionally been associated with motor control and perception, but a broader role in cognitive function—including language processing—and behavior is now appreciated (Booth et al., 2007, Mariën et al., 2014). Intriguingly, the cerebellum has undergone rapid expansion in the great ape lineage (Barton and Venditti, 2014), and modern humans possess proportionally larger cerebella (greater cerebellum to total brain volume ratio) than did Neanderthals (Hublin et al., 2015)."
"Mutations and polymorphisms in this gene have been associated with a range of neuropsychiatric and neurological disorders including depression (Juhasz et al., 2011), suicide attempts (Murphy et al., 2011, Kohli et al., 2010), impaired speech and language development (Yeo et al., 2004), severe obesity (Gray et al., 2007), autism (Correia et al., 2010), obsessive-compulsive disorder (Alonso et al., 2008), Alzheimer’s disease (Chen et al., 2008), anorexia nervosa (Ribases et al., 2005), nicotine dependence (Li et al., 2008, Beuten et al., 2007), and pilocytic astrocytoma (Jones et al., 2013). Intriguingly, NTRK2 is among a small set of brain-specific genes whose regulatory domains overlap signatures of modern human selective sweeps that occurred after divergence from Neanderthals (Peyrégne et al., 2016)."
"Testis-expressed genes exemplifying the broader pattern of downregulation of Neanderthal alleles include DNALI1 (rs41267319, binomial GLMM: β = −0.476, 95% CI [−0.519, −0.432], p < 10−10, MAFEUR = 0.055), which encodes an axonemal dynein protein that functions in the sperm flagella. Highlighting the potential fitness consequences of introgression on testis-expressed genes, altered regulation of this gene set has been shown to contribute to hybrid incompatibility in other species (Turner and Harr, 2014). Consistent with this observation, genes with high expression in the testes are significantly depleted of Neanderthal ancestry, suggesting that purifying selection disproportionately removed Neanderthal haplotypes at these genes following introgression (Sankararaman et al., 2014). This finding is also consistent with the hypothesis that male hybrid individuals may have incurred reduced fertility (Sankararaman et al., 2014, Sankararaman et al., 2016, Currat and Excoffier, 2011)."
