Genome-enabled inference of functional genetic variants in the face, brain and behavior

AbstractLake Malawi cichlid fishes exhibit extensive divergence in form and function among closely related species separated by a relatively small number of genetic changes. During the past million years, hundreds of species have diversified along an ecological axis in rock vs. sand habitats. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants in which genes differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. The majority of divergent coding variants are missense and/or loss of function. Regions near differentiated variants are enriched for craniofacial, neural and behavioral functional categories. To follow up experimentally, we used rock- vs. sand-species and their hybrids to (i) clarify the push-pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results suggest compelling ties between early brain development and adult behavior and highlight the promise of evolutionary reverse genetics – the identification of functional variants from genome sequencing in natural populations.

Download Full-text

Genome-enabled discovery of evolutionary divergence in brains and behavior

Scientific Reports ◽

10.1038/s41598-021-92385-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chinar Patil ◽

Jonathan B. Sylvester ◽

Kawther Abdilleh ◽

Michael W. Norsworthy ◽

Karen Pottin ◽

...

Keyword(s):

Reverse Genetics ◽

Natural Populations ◽

Bmp Signaling ◽

Evolutionary Divergence ◽

Genetic Changes ◽

Form And Function ◽

Brain Gene Expression ◽

Evolutionarily Conserved ◽

And Function ◽

And Behavior

AbstractLake Malawi cichlid fishes exhibit extensive divergence in form and function built from a relatively small number of genetic changes. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. Genome regions near differentiated variants are enriched for craniofacial, neural and behavioral categories. Following leads from genome sequence, we used rock- vs. sand-species and their hybrids to (i) delineate the push–pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results demonstrate how divergent genome sequences can predict differences in key evolutionary traits. We highlight the promise of evolutionary reverse genetics—the inference of phenotypic divergence from unbiased genome sequencing and then empirical validation in natural populations.

Download Full-text

Genome-enabled discovery of evolutionary divergence in brains and behavior

10.21203/rs.3.rs-275291/v1 ◽

2021 ◽

Author(s):

Chinar Patil ◽

Jonathan Sylvester ◽

Kawther Abdilleh ◽

Michael W. Norsworthy ◽

Karen Pottin ◽

...

Keyword(s):

Reverse Genetics ◽

Natural Populations ◽

Bmp Signaling ◽

Evolutionary Divergence ◽

Genetic Changes ◽

Form And Function ◽

Brain Gene Expression ◽

Evolutionarily Conserved ◽

And Function ◽

And Behavior

Abstract Lake Malawi cichlid fishes exhibit extensive divergence in form and function built from a relatively small number of genetic changes. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. Genome regions near differentiated variants are enriched for craniofacial, neural and behavioral categories. Following leads from genome sequence, we used rock- vs. sand- species and their hybrids to (i) delineate the push-pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results demonstrate how divergent genome sequences can predict differences in key evolutionary traits. We highlight the promise of evolutionary reverse genetics – the inference of divergence in phenotype from genome sequencing in natural populations.

Download Full-text

Evaluation of the functional effects of genetic variants‒missense and nonsense SNPs, indels and copy number variations‒in the gene encoding human deoxyribonuclease I potentially implicated in autoimmunity

Scientific Reports ◽

10.1038/s41598-019-49935-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Misuzu Ueki ◽

Kaori Kimura-Kataoka ◽

Junko Fujihara ◽

Reiko Iida ◽

Yasuyuki Kawai ◽

...

Keyword(s):

Genetic Variants ◽

Copy Number ◽

Marked Reduction ◽

Copy Number Variations ◽

Dnase I ◽

The Other ◽

Loss Of Function ◽

Ensembl Database ◽

Deoxyribonuclease I ◽

Functional Variants

Abstract Genetic variants, such as single nucleotide polymorphisms (SNPs), in the deoxyribonuclease I (DNase I) gene which remarkably reduce or abolish the activity are assumed to be substantially responsible for the genetic backgrounds determining susceptibility to autoimmune dysfunction. Here, we evaluated many genetic variants, including missense and nonsense SNPs, and indel (inframe) variants in the gene, potentially implicated in autoimmune diseases as functional variants resulting in altered activity levels. Eighteen missense and 7 nonsense SNPs, and 9 indel (inframe) variants were found to result in loss of function and disappearance of DNase I activity. Furthermore, considering the positions in the DNase I protein corresponding to the various nonsense SNPs, all of the other nonsense SNPs and frameshift variants registered in the Ensembl database (https://asia.ensembl.org) appear likely to exert a pathogenetic effect through loss of the activity. Accordingly, a total of 60 genetic variants in the DNase 1 gene (DNASE1) inducing abolishment or marked reduction of the DNase I activity could be identified as genetic risk factors for autoimmunity, irrespective of how sparsely they were distributed in the population. It was noteworthy that SNP p.Gln244Arg, reportedly associated with autoimmunity and reducing the activity to about half of that of the wild type, and SNP p.Arg107Gly, abolishing the activity completely, were distributed worldwide and in African populations at the polymorphic level, respectively. On the other hand, with regard to copy number variations in DNASE1 where loss of copy leads to a reduction of the in vivo enzyme activity, only 2 diploid copy numbers were distributed in Japanese and German populations, demonstrating no loss of copy. These exhaustive data for genetic variants in DNASE1 resulting in loss or marked reduction of the DNase I activity are highly informative when considering genetic predisposition leading to autoimmune dysfunction.

Download Full-text

Many human accelerated regions are developmental enhancers

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0025 ◽

2013 ◽

Vol 368 (1632) ◽

pp. 20130025 ◽

Cited By ~ 98

Author(s):

John A. Capra ◽

Genevieve D. Erwin ◽

Gabriel McKinsey ◽

John L. R. Rubenstein ◽

Katherine S. Pollard

Keyword(s):

Expression Patterns ◽

Regulatory Sequences ◽

Genetic Changes ◽

Form And Function ◽

Regulatory Changes ◽

Chimpanzee Sequence ◽

And Function ◽

Regulatory Functions ◽

Human Accelerated Regions ◽

Human Specific

The genetic changes underlying the dramatic differences in form and function between humans and other primates are largely unknown, although it is clear that gene regulatory changes play an important role. To identify regulatory sequences with potentially human-specific functions, we and others used comparative genomics to find non-coding regions conserved across mammals that have acquired many sequence changes in humans since divergence from chimpanzees. These regions are good candidates for performing human-specific regulatory functions. Here, we analysed the DNA sequence, evolutionary history, histone modifications, chromatin state and transcription factor (TF) binding sites of a combined set of 2649 non-coding human accelerated regions (ncHARs) and predicted that at least 30% of them function as developmental enhancers. We prioritized the predicted ncHAR enhancers using analysis of TF binding site gain and loss, along with the functional annotations and expression patterns of nearby genes. We then tested both the human and chimpanzee sequence for 29 ncHARs in transgenic mice, and found 24 novel developmental enhancers active in both species, 17 of which had very consistent patterns of activity in specific embryonic tissues. Of these ncHAR enhancers, five drove expression patterns suggestive of different activity for the human and chimpanzee sequence at embryonic day 11.5. The changes to human non-coding DNA in these ncHAR enhancers may modify the complex patterns of gene expression necessary for proper development in a human-specific manner and are thus promising candidates for understanding the genetic basis of human-specific biology.

Download Full-text

Scanning tunneling microscopy (STM) of DNA and RNA

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100152148 ◽

1989 ◽

Vol 47 ◽

pp. 34-35

Author(s):

Patricia G. Arscott ◽

Gil Lee ◽

Victor A. Bloomfield ◽

D. Fennell Evans

Keyword(s):

Molecular Structures ◽

Inorganic Materials ◽

Resolving Power ◽

Scanning Tunneling ◽

Tunneling Microscopy ◽

Form And Function ◽

Dna And Rna ◽

Calf Thymus ◽

And Function ◽

The Relationship

STM is one of the most promising techniques available for visualizing the fine details of biomolecular structure. It has been used to map the surface topography of inorganic materials in atomic dimensions, and thus has the resolving power not only to determine the conformation of small molecules but to distinguish site-specific features within a molecule. That level of detail is of critical importance in understanding the relationship between form and function in biological systems. The size, shape, and accessibility of molecular structures can be determined much more accurately by STM than by electron microscopy since no staining, shadowing or labeling with heavy metals is required, and there is no exposure to damaging radiation by electrons. Crystallography and most other physical techniques do not give information about individual molecules.We have obtained striking images of DNA and RNA, using calf thymus DNA and two synthetic polynucleotides, poly(dG-me5dC)·poly(dG-me5dC) and poly(rA)·poly(rU).

Download Full-text