scholarly journals Contribution of retrotransposition to developmental disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Protein Coding ◽  
Genome Wide ◽  
De Novo Gene ◽  
The Impact ◽  
Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

scholarly journals Contribution of Retrotransposition to Developmental Disorders

2018 ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Mobile Genetic Elements ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Genome Wide ◽  
The Impact ◽  
Transcribed Sequences

AbstractMobile genetic Elements (MEs) are segments of DNA which, through an RNA intermediate, can generate new copies of themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. As such, we have identified RT-derived events in 9,738 exome sequenced trios with DD-affected probands as part of the Deciphering Developmental Disorders (DDD) study. We have ascertained 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04% of probands), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we have estimated genome-wide germline ME mutagenesis and constraint and demonstrated that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

scholarly journals Sex-biased reduction in reproductive success drives selective constraint on human genes

2020 ◽  
Author(s):  
Eugene J. Gardner ◽  
Matthew D. C. Neville ◽  
Kaitlin E. Samocha ◽  
Kieron Barclay ◽  
Martin Kolk ◽  
...  
Keyword(s):  
Sexual Selection ◽  
Reproductive Success ◽  
Genetic Variants ◽  
Purifying Selection ◽  
Female Mate Choice ◽  
Selective Constraint ◽  
Human Populations ◽  
Protein Coding ◽  
Genome Wide ◽  
Human Genes

SummaryGenome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. While genes under the strongest selective constraint are highly enriched for Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show that genetic variants that damage these genes reduce reproductive success substantially in males but much less so in females. We present evidence that this reduction is mediated primarily by cognitive and behavioural traits, which renders male carriers of such variants less likely to find mating partners. These findings represent strong genetic evidence that sexual selection mediated through female mate choice is shaping the gene pool of contemporary human populations. Furthermore, these results suggest that sexual selection accounts for 21% of purifying selection against heterozygous variants that ablate protein-coding genes.

scholarly journals The morphogenetic role of midline mesendoderm and ectoderm in the development of the forebrain and the midbrain of the mouse embryo

Development ◽  
2000 ◽  
Vol 127 (9) ◽  
pp. 1799-1813 ◽  
Author(s):  
A. Camus ◽  
B.P. Davidson ◽  
S. Billiards ◽  
P. Khoo ◽  
J.A. Rivera-Perez ◽  
...  
Keyword(s):  
Neural Tube ◽  
Mouse Embryo ◽  
De Novo ◽  
Gene Activity ◽  
Anteroposterior Patterning ◽  
De Novo Gene ◽  
Ventral Neural Tube ◽  
And Function ◽  
The Impact

The anterior midline tissue (AML) of the late gastrula mouse embryo comprises the axial mesendoderm and the ventral neuroectoderm of the prospective forebrain, midbrain and rostral hindbrain. In this study, we have investigated the morphogenetic role of defined segments of the AML by testing their inductive and patterning activity and by assessing the impact of their ablation on the patterning of the neural tube at the early-somite-stage. Both rostral and caudal segments of the AML were found to induce neural gene activity in the host tissue; however, the de novo gene activity did not show any regional characteristic that might be correlated with the segmental origin of the AML. Removal of the rostral AML that contains the prechordal plate resulted in a truncation of the head accompanied by the loss of several forebrain markers. However, the remaining tissues reconstituted Gsc and Shh activity and expressed the ventral forebrain marker Nkx2.1. Furthermore, analysis of Gsc-deficient embryos reveals that the morphogenetic function of the rostral AML requires Gsc activity. Removal of the caudal AML led to a complete loss of midline molecular markers anterior to the 4th somite. In addition, Nkx2.1 expression was not detected in the ventral neural tube. The maintenance and function of the rostral AML therefore require inductive signals emanating from the caudal AML. Our results point to a role for AML in the refinement of the anteroposterior patterning and morphogenesis of the brain.

scholarly journals Pathogenicity and selective constraint on variation near splice sites

2018 ◽  
Author(s):  
Jenny Lord ◽  
Giuseppe Gallone ◽  
Patrick J. Short ◽  
Jeremy F. McRae ◽  
Holly Ironfield ◽  
...  
Keyword(s):  
Splice Site ◽  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Splice Sites ◽  
Sequencing Data ◽  
Pathogenic Variants ◽  
Unbiased Manner ◽  
Functional Relevance

AbstractMutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.

scholarly journals Quantifying the contribution of recessive coding variation to developmental disorders

Science ◽  
2018 ◽  
Vol 362 (6419) ◽  
pp. 1161-1164 ◽  
Author(s):  
Hilary C. Martin ◽  
Wendy D. Jones ◽  
Rebecca McIntyre ◽  
Gabriela Sanchez-Andrade ◽  
Mark Sanderson ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
European Ancestry ◽  
Incomplete Penetrance ◽  
Cellular Models ◽  
Genome Wide ◽  
Coding Variants

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

scholarly journals Protein Coding Gene Nucleotide Substitution Pattern in the Apicomplexan ProtozoaCryptosporidium parvumandCryptosporidium hominis

2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Guangtao Ge ◽  
Lenore Cowen ◽  
Xiaochuan Feng ◽  
Giovanni Widmer
Keyword(s):  
Positive Selection ◽  
Purifying Selection ◽  
High Ratio ◽  
Genome Comparison ◽  
Nucleotide Substitutions ◽  
Substitution Pattern ◽  
Protein Coding ◽  
Genome Wide ◽  
The Impact ◽  
Selection Of

Cryptosporidium parvumandC. hominisare related protozoan pathogens which infect the intestinal epithelium of humans and other vertebrates. To explore the evolution of these parasites, and identify genes under positive selection, we performed a pairwise whole-genome comparison between all orthologous protein coding genes inC. parvumandC. hominis. Genome-wide calculation of the ratio of nonsynonymous versus synonymous nucleotide substitutions (dN/dS) was performed to detect the impact of positive and purifying selection. Of 2465 pairs of orthologous genes, a total of 27 (1.1%) showed a high ratio of nonsynonymous substitutions, consistent with positive selection. A majority of these genes were annotated as hypothetical proteins. In addition, proteins with transmembrane and signal peptide domains are significantly more frequent in the highdN/dSgroup.

scholarly journals A map of constrained coding regions in the human genome

2017 ◽  
Author(s):  
James M. Havrilla ◽  
Brent S. Pedersen ◽  
Ryan M. Layer ◽  
Aaron R. Quinlan
Keyword(s):  
Human Genome ◽  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Protein Domain ◽  
De Novo Mutations ◽  
Protein Coding ◽  
Constrained Coding ◽  
Coding Regions ◽  
Pathogenic Variants

ABSTRACTDeep catalogs of genetic variation collected from many thousands of humans enable the detection of intraspecies constraint by revealing coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single metrics cannot capture the fine-scale variability in constraint within each protein-coding gene. To provide greater resolution, we have created a detailed map of constrained coding regions (CCRs) in the human genome by leveraging coding variation observed among 123,136 humans from the Genome Aggregation Database (gnomAD). The most constrained coding regions in our map are enriched for both pathogenic variants in ClinVar and de novo mutations underlying developmental disorders. CCRs also reveal protein domain families under high constraint, suggest unannotated or incomplete protein domains, and facilitate the prioritization of previously unseen variation in studies of disease. Finally, a subset of CCRs with the highest constraint likely exist within genes that cause yet unobserved human phenotypes owing to strong purifying selection.

scholarly journals Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

2019 ◽  
Author(s):  
Joanna Kaplanis ◽  
Kaitlin E. Samocha ◽  
Laurens Wiel ◽  
Zhancheng Zhang ◽  
Kevin J. Arvai ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Genetic Data ◽  
Statistical Test ◽  
Integrated Healthcare ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Clinical Diagnostic ◽  
Simulation Based

SummaryDe novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

scholarly journals The Genomic Ecosystem of Transposable Elements in Maize

2019 ◽  
Author(s):  
Michelle C. Stitzer ◽  
Sarah N. Anderson ◽  
Nathan M. Springer ◽  
Jeffrey Ross-Ibarra
Keyword(s):  
Transposable Elements ◽  
Evolutionary Dynamics ◽  
Phenotypic Diversity ◽  
Flowering Plant ◽  
Genome Wide ◽  
Family Level ◽  
Genomic Environment ◽  
Single Category ◽  
The Impact

Transposable elements (TEs) constitute the majority of flowering plant DNA, reflecting their tremendous success in subverting, avoiding, and surviving the defenses of their host genomes to ensure their selfish replication. More than 85% of the sequence of the maize genome can be ascribed to past transposition, providing a major contribution to the structure of the genome. Evidence from individual loci has informed our understanding of how transposition has shaped the genome, and a number of individual TE insertions have been causally linked to dramatic phenotypic changes. But genome-wide analyses in maize and other taxa have frequently represented TEs as a relatively homogeneous class of fragmentary relics of past transposition, obscuring their evolutionary history and interaction with their host genome. Using an updated annotation of structurally intact TEs in the maize reference genome, we investigate the family-level ecological and evolutionary dynamics of TEs in maize. Integrating a variety of data, from descriptors of individual TEs like coding capacity, expression, and methylation, as well as similar features of the sequence they inserted into, we model the relationship between these attributes of the genomic environment and the survival of TE copies and families. Our analyses reveal a diversity of ecological strategies of TE families, each representing the evolution of a distinct ecological niche allowing survival of the TE family. In contrast to the wholesale relegation of all TEs to a single category of junk DNA, these differences generate a rich ecology of the genome, suggesting families of TEs that coexist in time and space compete and cooperate with each other. We conclude that while the impact of transposition is highly family- and context-dependent, a family-level understanding of the ecology of TEs in the genome can refine our ability to predict the role of TEs in generating genetic and phenotypic diversity.‘Lumping our beautiful collection of transposons into a single category is a crime’-Michael R. Freeling, Mar. 10, 2017

scholarly journals Assessing Genome-Wide Diversity in European Hantaviruses through Sequence Capture from Natural Host Samples

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 749 ◽  
Author(s):  
Melanie Hiltbrunner ◽  
Gerald Heckel
Keyword(s):  
High Throughput Sequencing ◽  
De Novo ◽  
Phylogenetic Analyses ◽  
Common Vole ◽  
Natural Host ◽  
Sequence Information ◽  
Coding Region ◽  
Sequence Capture ◽  
Genome Wide ◽  
The Impact

Research on the ecology and evolution of viruses is often hampered by the limitation of sequence information to short parts of the genomes or single genomes derived from cultures. In this study, we use hybrid sequence capture enrichment in combination with high-throughput sequencing to provide efficient access to full genomes of European hantaviruses from rodent samples obtained in the field. We applied this methodology to Tula (TULV) and Puumala (PUUV) orthohantaviruses for which analyses from natural host samples are typically restricted to partial sequences of their tri-segmented RNA genome. We assembled a total of ten novel hantavirus genomes de novo with very high coverage (on average >99%) and sequencing depth (average >247×). A comparison with partial Sanger sequences indicated an accuracy of >99.9% for the assemblies. An analysis of two common vole (Microtus arvalis) samples infected with two TULV strains each allowed for the de novo assembly of all four TULV genomes. Combining the novel sequences with all available TULV and PUUV genomes revealed very similar patterns of sequence diversity along the genomes, except for remarkably higher diversity in the non-coding region of the S-segment in PUUV. The genomic distribution of polymorphisms in the coding sequence was similar between the species, but differed between the segments with the highest sequence divergence of 0.274 for the M-segment, 0.265 for the S-segment, and 0.248 for the L-segment (overall 0.258). Phylogenetic analyses showed the clustering of genome sequences consistent with their geographic distribution within each species. Genome-wide data yielded extremely high node support values, despite the impact of strong mutational saturation that is expected for hantavirus sequences obtained over large spatial distances. We conclude that genome sequencing based on capture enrichment protocols provides an efficient means for ecological and evolutionary investigations of hantaviruses at an unprecedented completeness and depth.

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