Natural variation in abiotic stress responsive gene expression and local adaptation to climate in Arabidopsis thaliana.

Gene expression varies widely in natural populations, yet the proximate and ultimate causes of this variation are poorly known. Understanding how variation in gene expression affects abiotic stress tolerance, fitness, and adaptation is central to the field of evolutionary genetics. We tested the hypothesis that genes with natural genetic variation in their expression responses to abiotic stress are likely to be involved in local adaptation to climate in Arabidopsis thaliana. Specifically, we compared genes with consistent expression responses to environmental stress (expression stress responsive, "eSR") to genes with genetically variable responses to abiotic stress (expression genotype-by-environment interaction, "eGEI"). We found that on average genes that exhibited eGEI in response to drought or cold had greater polymorphism in promoter regions and stronger associations with climate than those of eSR genes or genomic controls. We also found that transcription factor binding sites known to respond to environmental stressors, especially abscisic acid responsive elements, showed significantly higher polymorphism in drought eGEI genes in comparison to eSR genes. By contrast, eSR genes tended to exhibit relatively greater pairwise haplotype sharing, lower promoter diversity, and fewer nonsynonymous polymorphisms, suggesting purifying selection or selective sweeps. Our results indicate that cis-regulatory evolution and genetic variation in stress responsive gene expression may be important mechanisms of local adaptation to climatic selective gradients

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.Peer reviewe

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Context dependent selection in molecular evolution

Se ha predicho teóreticamente que la epistasis, es decir, las interacciones genéticas entre diferentes mutaciones, cumple un rol sustancial en procesos evolutivos, tales como la emergencia de la reproducción sexual, la recombinación, la especiación y la evolución adaptativa. Sin embargo, existe poca evidencia experimental o estadística de la ubicuidad de las interacciones epistáticas en la naturaleza. Aquí, estudiamos la evolución de las proteínas a largo plazo, y demostramos que el modelo constante de selección independiente, no es capaz de describir las tasas y patrones de divergencia encontrados en las proteínas: las proteínas divergen mas allá de los límites teóricos y la tasa de divergencia es mucho mas lenta que la esperada. A su vez, demostramos que la evolución de las proteínas se explica mejor bajo la suposición de un intercambio rápido entre los valores de eficacia biológica asociados con aminoácidos individuales. Mas aún, extendemos nuestro estudio computacional y construimos un modelo teórico que captura el efecto de la selección inconstante sobre la evolución molecular.Epistasis, or genetic interactions between different mutations, is theoretically predicted to play a substantial role in such evolutionary processes as emergence of sexual reproduction and recombination, speciation, adaptive evolution. However, there is little experimental or statistical evidence of the ubiquity of epistatic interactions in nature. Here, we study long-term protein evolution and show that the constant independent selection model cannot describe rates and patterns of protein divergence: protein sequences diverge beyond theoretical limits and the rate of divergence is much slower than predicted. We show that protein evolution is best explained under the assumption of rapid turnover of fitness values associated with individual amino acids. We further extend this computational study and build a theoretical model to capture the effect of non-constant selection on molecular evolution

Context dependent selection in molecular evolution

Se ha predicho teóreticamente que la epistasis, es decir, las interacciones genéticas entre diferentes mutaciones, cumple un rol sustancial en procesos evolutivos, tales como la emergencia de la reproducción sexual, la recombinación, la especiación y la evolución adaptativa. Sin embargo, existe poca evidencia experimental o estadística de la ubicuidad de las interacciones epistáticas en la naturaleza. Aquí, estudiamos la evolución de las proteínas a largo plazo, y demostramos que el modelo constante de selección independiente, no es capaz de describir las tasas y patrones de divergencia encontrados en las proteínas: las proteínas divergen mas allá de los límites teóricos y la tasa de divergencia es mucho mas lenta que la esperada. A su vez, demostramos que la evolución de las proteínas se explica mejor bajo la suposición de un intercambio rápido entre los valores de eficacia biológica asociados con aminoácidos individuales. Mas aún, extendemos nuestro estudio computacional y construimos un modelo teórico que captura el efecto de la selección inconstante sobre la evolución molecular.Epistasis, or genetic interactions between different mutations, is theoretically predicted to play a substantial role in such evolutionary processes as emergence of sexual reproduction and recombination, speciation, adaptive evolution. However, there is little experimental or statistical evidence of the ubiquity of epistatic interactions in nature. Here, we study long-term protein evolution and show that the constant independent selection model cannot describe rates and patterns of protein divergence: protein sequences diverge beyond theoretical limits and the rate of divergence is much slower than predicted. We show that protein evolution is best explained under the assumption of rapid turnover of fitness values associated with individual amino acids. We further extend this computational study and build a theoretical model to capture the effect of non-constant selection on molecular evolution

Stop codons in bacteria are not selectively equivalent

Background: The evolution and genomic stop codon frequencies have not been rigorously studied with the exception of coding of non-canonical amino acids. Here we study the rate of evolution and frequency distribution of stop codons in bacterial genomes. Results: We show that in bacteria stop codons evolve slower than synonymous sites, suggesting the action of weak negative selection. However, the frequency of stop codons relative to genomic nucleotide content indicated that this selection regime is not straightforward. The frequency of TAA and TGA stop codons is GC-content dependent, with TAA decreasing and TGA increasing with GC-content, while TAG frequency is independent of GC-content. Applying a formal, analytical model to these data we found that the relationship between stop codon frequencies and nucleotide content cannot be explained by mutational biases or selection on nucleotide content. However, with weak nucleotide content-dependent selection on TAG, -0.5  16% TGA has a higher fitness than TAG. Conclusions: Our data indicate that TAG codon is universally suboptimal in the bacterial lineage, such that TAA is likely to be the preferred stop codon for low GC content while the TGA is the preferred stop codon for high GC content. The optimization of stop codon usage may therefore be useful in genome engineering or gene expression optimization applications.The work has been supported by a Plan Nacional grant from the Spanish Ministry of Science and Innovation, EMBO Young Investigator and Howard Hughes Medical Institute International Early Career Scientist awards

Rate of sequence divergence under constant selection

BACKGROUND: Divergence of two independently evolving sequences that originated from a common ancestor can be described by two parameters, the asymptotic level of divergence E and the rate r at which this level of divergence is approached. Constant negative selection impedes allele replacements and, therefore, is routinely assumed to decelerate sequence divergence. However, its impact on E and on r has not been formally investigated. RESULTS: Strong selection that favors only one allele can make E arbitrarily small and r arbitrarily large. In contrast, in the case of 4 possible alleles and equal mutation rates, the lowest value of r, attained when two alleles confer equal fitnesses and the other two are strongly deleterious, is only two times lower than its value under selective neutrality. CONCLUSIONS: Constant selection can strongly constrain the level of sequence divergence, but cannot reduce substantially the rate at which this level is approached. In particular, under any constant selection the divergence of sequences that accumulated one substitution per neutral site since their origin from the common ancestor must already constitute at least one half of the asymptotic divergence at sites under such selectio

Stop codons in bacteria are not selectively equivalent

Background: The evolution and genomic stop codon frequencies have not been rigorously studied with the exception of coding of non-canonical amino acids. Here we study the rate of evolution and frequency distribution of stop codons in bacterial genomes. Results: We show that in bacteria stop codons evolve slower than synonymous sites, suggesting the action of weak negative selection. However, the frequency of stop codons relative to genomic nucleotide content indicated that this selection regime is not straightforward. The frequency of TAA and TGA stop codons is GC-content dependent, with TAA decreasing and TGA increasing with GC-content, while TAG frequency is independent of GC-content. Applying a formal, analytical model to these data we found that the relationship between stop codon frequencies and nucleotide content cannot be explained by mutational biases or selection on nucleotide content. However, with weak nucleotide content-dependent selection on TAG, -0.5  16% TGA has a higher fitness than TAG. Conclusions: Our data indicate that TAG codon is universally suboptimal in the bacterial lineage, such that TAA is likely to be the preferred stop codon for low GC content while the TGA is the preferred stop codon for high GC content. The optimization of stop codon usage may therefore be useful in genome engineering or gene expression optimization applications.The work has been supported by a Plan Nacional grant from the Spanish Ministry of Science and Innovation, EMBO Young Investigator and Howard Hughes Medical Institute International Early Career Scientist awards