scholarly journals Many human accelerated regions are developmental enhancers

2013 ◽  
Vol 368 (1632) ◽  
pp. 20130025 ◽  
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.

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

2020 ◽  
Author(s):  
Chinar Patil ◽  
Jonathan B. Sylvester ◽  
Kawther Abdilleh ◽  
Michael W. Norsworthy ◽  
Karen Pottin ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Reverse Genetics ◽  
Natural Populations ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Genetic Changes ◽  
Form And Function ◽  
Functional Variants ◽  
Brain And Behavior ◽  
And Function

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.

scholarly journals Genome-enabled discovery of evolutionary divergence in brains and behavior

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.

scholarly journals Identification of Novel Putative Regulatory Genes Induced During Alfalfa Nodule Development with a Cold-Plaque Screening Procedure

1998 ◽  
Vol 11 (5) ◽  
pp. 358-366 ◽  
Author(s):  
Florian Frugier ◽  
Adam Kondorosi ◽  
Martin Crespi
Keyword(s):  
Expression Patterns ◽  
Protein A ◽  
Screening Method ◽  
Screening Procedure ◽  
Nodule Development ◽  
Stage Of Development ◽  
Plant Genes ◽  
Gene Transcripts ◽  
And Function ◽  
Regulatory Functions

Until now very few plant genes with possible regulatory functions during nodule development have been isolated. We have used a modified cold-plaque screening method to identify new transcripts expressed at low levels that are induced during nodulation. Several clones were isolated and characterized by their mRNA expression patterns during nodule development and in spontaneous nodules. Sequence homology with known genes of other organisms indicated that transcripts corresponded to (i) “basic” genes probably required during the growth of the nodule organ (e.g., structural proteins), (ii) genes related to the metabolic adaptations taking place during nodule morphogenesis and function (e.g., carbonic anhydrase), and (iii) genes containing regulatory motifs and/or homologies (three clones out of the 20 identified). The latter genes encode a zinc-finger-containing protein, a putative protein kinase, and a Wilm's tumor (WT) suppressor homologue, respectively. Expression of the kinase and WT suppressor homologues was induced early in nodulation, although the latter was activated transiently. Accumulation of the Zn-finger gene transcripts was detected at a later stage of development and seems to be regulated in a complex manner. Hence, using a cold-plaque screening procedure, we could identify genes that may play regulatory roles in the signal transduction pathways activated during nodule development.

scholarly journals Genome-enabled discovery of evolutionary divergence in brains and behavior 

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.

scholarly journals Massively parallel discovery of human-specific substitutions that alter enhancer activity

2020 ◽  
Vol 118 (2) ◽  
pp. e2007049118
Author(s):  
Severin Uebbing ◽  
Jake Gockley ◽  
Steven K. Reilly ◽  
Acadia A. Kocher ◽  
Evan Geller ◽  
...  
Keyword(s):  
Human Evolution ◽  
Regulatory Elements ◽  
Massively Parallel ◽  
Enhancer Activity ◽  
Genetic Changes ◽  
Gene Regulatory Elements ◽  
Enhancer Function ◽  
Human Accelerated Regions ◽  
The Impact ◽  
Human Specific

Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of human traits such as the expansion of the cerebral cortex. However, identifying the particular changes that modified regulatory activity during human evolution remain challenging. Here we used massively parallel enhancer assays in neural stem cells to quantify the functional impact of >32,000 human-specific substitutions in >4,300 human accelerated regions (HARs) and human gain enhancers (HGEs), which include enhancers with novel activities in humans. We found that >30% of active HARs and HGEs exhibited differential activity between human and chimpanzee. We isolated the effects of human-specific substitutions from background genetic variation to identify the effects of genetic changes most relevant to human evolution. We found that substitutions interacted in both additive and nonadditive ways to modify enhancer function. Substitutions within HARs, which are highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions is buffered in enhancers with constrained ancestral functions. Our findings yield insight into how human-specific genetic changes altered enhancer function and provide a rich set of candidates for studies of regulatory evolution in humans.

Limb type-specific regulation of bric a brac contributes to morphological diversity

Development ◽  
2002 ◽  
Vol 129 (3) ◽  
pp. 695-704
Author(s):  
Jessie Chu ◽  
P. D. Si Dong ◽  
Grace Panganiban
Keyword(s):  
Expression Patterns ◽  
Morphological Difference ◽  
Morphological Diversity ◽  
Distal Portion ◽  
Specific Expression ◽  
Morphological Variations ◽  
Form And Function ◽  
Specific Regulation ◽  
And Function ◽  
Insect Antenna

The insect antenna and leg are considered homologous structures, likely to have arisen via duplication and divergence from an ancestral limb. Consistent with this, the antenna and leg are derived from primordia with similar developmental potentials. Nonetheless, the adult structures differ in both form and function. In Drosophila, one conspicuous morphological difference is that the antenna has fewer distal segments than the leg. We propose that this is due in part to the variations in the regulation of bric a brac. bric a brac is required for joint formation, and loss of bric a brac function leads to fusion of distal antennal and leg segments, resulting in fewer total segments. Here, we address how bric a brac is regulated to generate the mature expression patterns of two concentric rings in the antenna versus four concentric rings in the leg. We find that bric a brac expression is activated early throughout most of the Distal-less domain in both antenna and leg and subsequently is restricted to the distal portion and into rings. Although bric a brac expression in the antenna and in all four tarsal rings of the leg requires Distal-less, only the proximal three tarsal rings are Spineless-dependent. Thus bric a brac is regulated differentially even within a single appendage type. The restriction of bric a brac expression to the distal portion of the Distal-less domain is a consequence of negative regulation by distinct sets of genes in different limb types. In the leg, the proximal boundary of bric a brac is established by the medial-patterning gene dachshund, but dachshund alone is insufficient to repress bric a brac, and the expression of the two genes overlaps. In the antenna, the proximal boundary of bric a brac is established by an antenna-specifying gene, homothorax, in conjunction with dachshund and spalt, and there is much less overlap between the bric a brac and the dachshund domains. Thus tissue-specific expression of other patterning genes that differentially repress bric a brac accounts for antenna-leg differences in bric a brac pattern. We propose that the limb type-specific variations in expression of bric a brac repressors contribute to morphological variations by controlling distal limb segment number.

scholarly journals Massively parallel discovery of human-specific substitutions that alter neurodevelopmental enhancer activity

2019 ◽  
Author(s):  
Severin Uebbing ◽  
Jake Gockley ◽  
Steven K. Reilly ◽  
Acadia A. Kocher ◽  
Evan Geller ◽  
...  
Keyword(s):  
Binding Sites ◽  
Experimental Studies ◽  
Regulatory Elements ◽  
Massively Parallel ◽  
Enhancer Activity ◽  
Genetic Changes ◽  
Human Neural Stem Cells ◽  
Human Accelerated Regions ◽  
The Impact ◽  
Human Specific

AbstractGenetic changes that altered the function of gene regulatory elements have been implicated in the evolution of the human brain. However, identifying the particular changes that modified regulatory activity during neurodevelopment remains challenging. Here we used massively parallel enhancer assays in human neural stem cells to measure the impact of 32,776 human-specific substitutions on enhancer activity in 1,363 Human Accelerated Regions (HARs) and 3,027 Human Gain Enhancers (HGEs), which include enhancers with novel activities in humans. We found that 31.9% of active HARs and 36.4% of active HGEs exhibited differential activity between human and chimpanzee. This enabled us to isolate the effects of 401 human-specific substitutions from other types of genetic variation in HARs and HGEs. Substitutions acted in both an additive and non-additive manner to alter enhancer activity. Human-specific substitutions altered predicted binding sites for a specific set of human transcription factors (TFs) that were a subset of TF binding sites associated with enhancer activity in our assay. Substitutions within HARs, which are overall highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions may be buffered in enhancers with constrained ancestral functions. Our findings yield insight into the mechanisms by which human-specific genetic changes impact enhancer function and provide a rich set of candidates for experimental studies of regulatory evolution in humans.

scholarly journals Functional Analysis of the Polyketide Synthase Genes in the Filamentous Fungus Gibberella zeae (Anamorph Fusarium graminearum)

2005 ◽  
Vol 4 (11) ◽  
pp. 1926-1933 ◽  
Author(s):  
Iffa Gaffoor ◽  
Daren W. Brown ◽  
Ron Plattner ◽  
Robert H. Proctor ◽  
Weihong Qi ◽  
...  
Keyword(s):  
Filamentous Fungus ◽  
Polyketide Synthase ◽  
Expression Patterns ◽  
Gibberella Zeae ◽  
Plant Colonization ◽  
Type I ◽  
Form And Function ◽  
Single Organism ◽  
Complete Set ◽  
And Function

ABSTRACT Polyketides are a class of secondary metabolites that exhibit a vast diversity of form and function. In fungi, these compounds are produced by large, multidomain enzymes classified as type I polyketide synthases (PKSs). In this study we identified and functionally disrupted 15 PKS genes from the genome of the filamentous fungus Gibberella zeae. Five of these genes are responsible for producing the mycotoxins zearalenone, aurofusarin, and fusarin C and the black perithecial pigment. A comprehensive expression analysis of the 15 genes revealed diverse expression patterns during grain colonization, plant colonization, sexual development, and mycelial growth. Expression of one of the PKS genes was not detected under any of 18 conditions tested. This is the first study to genetically characterize a complete set of PKS genes from a single organism.

Scanning tunneling microscopy (STM) of DNA and RNA

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).

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