Fish and chips: the origin of human gene families is a predictor of the location of GWAS signals

Abstract GWAS have identified thousands of loci associated with human complex diseases and traits. How these loci are distributed through the genome has not been systematically evaluated. We hypothesised that the location of GWAS loci differ between ancestral linkage groups (ALGs) related to the paralogy and function of genes. We used data from the NHGRI-EBI GWAS catalog to determine whether the density of GWAS loci relative to HapMap variants in each ALG differed, and whether ALG’s were enriched for experimental factor ontological (EFO) terms assigned to the GWAS traits. In a gene-level analyses we explored the characteristics of genes linked to GWAS loci and those mapping to the ALG’s. We find that GWAS loci were enriched or deficient in 9 and 7 of the 17 ALG’s respectively, while there was no difference in the number of GWAS loci in regions of the human genome unassigned to an ALG. All but 2 ALG’s were significantly enriched or deficient for one or more EFO terms. Lastly, we find that genes assigned to an ALG are under higher levels of selective constraint, have longer coding sequences and higher median expression in the tissue of highest expression than genes not mapping to an ALG. On the other hand, genes associated with GWAS loci have longer genomic length and exhibit higher levels of selective constraint relative to non-GWAS genes.Collectively, this suggests that understanding the location and ancestral origins of GWAS signals may be informative for the development of tools for variant prioritization and interpretation.

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(TG/CA)n repeats in human gene families: abundance and selective patterns of distribution according to function and gene length

BMC Genomics ◽

10.1186/1471-2164-6-83 ◽

2005 ◽

Vol 6 (1) ◽

Cited By ~ 13

Author(s):

Vineet K Sharma ◽

Samir K Brahmachari ◽

Srinivasan Ramachandran

Keyword(s):

Human Gene ◽

Gene Families ◽

Gene Length ◽

Patterns Of Distribution

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Gene Families, Epistasis and the Amino Acid Preferences of Protein Homologs

Evolutionary Bioinformatics ◽

10.1177/1176934319870485 ◽

2019 ◽

Vol 15 ◽

pp. 117693431987048

Author(s):

Evandro Ferrada

Keyword(s):

Amino Acid ◽

Genetic Background ◽

Sequence Divergence ◽

Gene Families ◽

Structure And Function ◽

Sequence Evolution ◽

Systematic Analysis ◽

Fitness Effects ◽

Computational Work ◽

And Function

In order to preserve structure and function, proteins tend to preferentially conserve amino acids at particular sites along the sequence. Because mutations can affect structure and function, the question arises whether the preference of a protein site for a particular amino acid varies between protein homologs, and to what extent that variation depends on sequence divergence. Answering these questions can help in the development of models of sequence evolution, as well as provide insights on the dependence of the fitness effects of mutations on the genetic background of sequences, a phenomenon known as epistasis. Here, I comment on recent computational work providing a systematic analysis of the extent to which the amino acid preferences of proteins depend on the background mutations of protein homologs.

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Novel and Unexpected Functions of SGLTs

Physiology ◽

10.1152/physiol.00021.2017 ◽

2017 ◽

Vol 32 (6) ◽

pp. 435-443 ◽

Cited By ~ 13

Author(s):

Ernest M. Wright ◽

Chiara Ghezzi ◽

Donald D. F. Loo

Keyword(s):

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Glucose Sensor ◽

Human Gene ◽

Gene Families ◽

Major Facilitator Superfamily ◽

Sodium Glucose Cotransporter ◽

Major Facilitator ◽

Familial Renal Glucosuria ◽

Opening And Closing

It has been 30 years since the intestinal sodium glucose cotransporter SGLT1 was cloned, and, in the intervening years, there have been many advances that have influenced physiology and medicine. Among the first was that SGLT1 is the founding member of the human gene family SLC5, containing 11 diverse transporters and a glucose sensor. Equally surprising was that SGLTs are members of a structural family of cotransporters and exchangers in different gene families. This led to the conclusion that these proteins operate by a mechanism where transport involves the opening and closing of external and internal gates. The mechanism is shared by a wide variety of transporters in different structural families, e.g., the human facilitated glucose transporters (SLC2) in the huge major facilitator superfamily (MFS). Not surprising is the finding that mutations in Sglt genes cause the rare diseases glucose-galactose-malabsorption (GGM) and familial renal glucosuria (FRG). However, it was not envisaged that SGLT inhibitors would be used to treat diabetes mellitus, and these drugs may be able to treat cancer. Finally, in 2017, we have just learned that SGLT1 may be required to resist infection and to avoid recurrent pregnancy loss.

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Two Human Gene Families Display Preferences for Different Nucleotides and Have Distinct Codon Usage Patterns

Experimental and Clinical Immunogenetics ◽

10.1159/000019122 ◽

2000 ◽

Vol 17 (1) ◽

pp. 29-41

Author(s):

Christine Skerka ◽

Wolfgang O. Abel ◽

Peter F. Zipfel

Keyword(s):

Codon Usage ◽

Human Gene ◽

Gene Families ◽

Usage Patterns

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Exploring the Caenorhabditis elegans and Drosophila melanogaster genomes to understand neuropeptide and peptidase function

Biochemical Society Transactions ◽

10.1042/bst0280464 ◽

2000 ◽

Vol 28 (4) ◽

pp. 464-469 ◽

Cited By ~ 12

Author(s):

D. Coates ◽

R. Siviter ◽

R. E. Isaac

Keyword(s):

Drosophila Melanogaster ◽

Caenorhabditis Elegans ◽

Comparative Studies ◽

Gene Families ◽

Human Condition ◽

Form And Function ◽

And Function ◽

The Human Condition

Comparison of peptidase gene families in the newly released Drosophila melanogaster and Caenorhabditis elegans genomes highlights important differences in peptidase distributions with relevance to the evolution of both form and function in these two organisms and can help to identify the most appropriate model when using comparative studies relevant to the human condition.

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Age distribution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution

Nature Genetics ◽

10.1038/ng902 ◽

2002 ◽

Vol 31 (2) ◽

pp. 205-209 ◽

Cited By ~ 146

Author(s):

Xun Gu ◽

Yufeng Wang ◽

Jianying Gu

Keyword(s):

Human Gene ◽

Age Distribution ◽

Gene Families ◽

Vertebrate Evolution ◽

Small Scale

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The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water

10.1101/242230 ◽

2018 ◽

Cited By ~ 1

Author(s):

David Armisén ◽

Rajendhran Rajakumar ◽

Markus Friedrich ◽

Joshua B Benoit ◽

Hugh M. Robertson ◽

...

Keyword(s):

Insulin Receptors ◽

Gene Families ◽

Developmental Genetics ◽

Manual Annotation ◽

Gene Duplications ◽

Water Strider ◽

Protein Coding ◽

Genomic Changes ◽

Aquatic Bugs ◽

And Function

AbstractThe semi-aquatic bugs conquered water surfaces worldwide and occupy ponds, streams, lakes, mangroves, and even open oceans. As such, they inspired a range of scientific studies from ecology and evolution to developmental genetics and hydrodynamics of fluid locomotion. However, the lack of a representative water strider genome hinders thorough investigations of the mechanisms underlying the processes of adaptation and diversification in this group. Here we report the sequencing and manual annotation of the Gerris buenoi (G. buenoi) genome, the first water strider genome to be sequenced so far. G. buenoi genome is about 1 000Mb and the sequencing effort recovered 20 949 predicted protein-coding genes. Manual annotation uncovered a number of local (tandem and proximal) gene duplications and expansions of gene families known for their importance in a variety of processes associated with morphological and physiological adaptations to water surface lifestyle. These expansions affect key processes such as growth, vision, desiccation resistance, detoxification, olfaction and epigenetic components. Strikingly, the G. buenoi genome contains three Insulin Receptors, a unique case among metazoans, suggesting key changes in the rewiring and function of the insulin pathway. Other genomic changes include wavelength sensitivity shifts in opsin proteins likely in association with the requirements of vision in water habitats. Our findings suggest that local gene duplications might have had an important role during the evolution of water striders. These findings along with the G. buenoi genome open exciting research opportunities to understand adaptation and genome evolution of this unique hemimetabolous insect.

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The R2R3-MYB transcription factor family in Taxus chinensis: identification, characterization, expression profiling and posttranscriptional regulation analysis

PeerJ ◽

10.7717/peerj.8473 ◽

2020 ◽

Vol 8 ◽

pp. e8473

Author(s):

Xinling Hu ◽

Lisha Zhang ◽

Iain Wilson ◽

Fenjuan Shao ◽

Deyou Qiu

Keyword(s):

Transcription Factor ◽

Posttranscriptional Regulation ◽

Gene Families ◽

Myb Transcription Factor ◽

Taxus Chinensis ◽

Transcription Factor Family ◽

Myb Genes ◽

And Function ◽

R2r3 Myb

The MYB transcription factor family is one of the largest gene families playing regulatory roles in plant growth and development. The MYB family has been studied in a variety of plant species but has not been reported in Taxus chinensis. Here we identified 72 putative R2R3-MYB genes in T. chinensis using a comprehensive analysis. Sequence features, conversed domains and motifs were characterized. The phylogenetic analysis showed TcMYBs and AtMYBs were clustered into 36 subgroups, of which 24 subgroups included members from T. chinensis and Arabidopsis thaliana, while 12 subgroups were specific to one species. This suggests the conservation and specificity in structure and function of plant R2R3-MYBs. The expression of TcMYBs in various tissues and different ages of xylem were investigated. Additionally, miRNA-mediated posttranscriptional regulation analysis revealed that TcMYBs were the targets of miR858, miR159 and miR828, suggesting the posttranscriptional regulation of MYBs is highly conserved in plants. The results provide a basis for further study the role of TcMYBs in the regulation of secondary metabolites of T. chinensis.

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The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2007391117 ◽

2020 ◽

Vol 117 (38) ◽

pp. 23548-23556 ◽

Cited By ~ 1

Author(s):

Pankaj Sharma ◽

Elena Maklashina ◽

Gary Cecchini ◽

T. M. Iverson

Keyword(s):

Tca Cycle ◽

Covalent Attachment ◽

X Ray ◽

Complex Ii ◽

Functional Complex ◽

Assembly Factor ◽

Mature Enzyme ◽

And Function ◽

The Impact ◽

Human Complex

Mitochondrial complex II, also known as succinate dehydrogenase (SDH), is an integral-membrane heterotetramer (SDHABCD) that links two essential energy-producing processes, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. A significant amount of information is available on the structure and function of mature complex II from a range of organisms. However, there is a gap in our understanding of how the enzyme assembles into a functional complex, and disease-associated complex II insufficiency may result from incorrect function of the mature enzyme or from assembly defects. Here, we investigate the assembly of human complex II by combining a biochemical reconstructionist approach with structural studies. We report an X-ray structure of human SDHA and its dedicated assembly factor SDHAF2. Importantly, we also identify a small molecule dicarboxylate that acts as an essential cofactor in this process and works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA. This reorganizes the active site, which is located at the interface of these domains, and adjusts the pKaof SDHAR451so that covalent attachment of the flavin adenine dinucleotide (FAD) cofactor is supported. We analyze the impact of disease-associated SDHA mutations on assembly and identify four distinct conformational forms of the complex II flavoprotein that we assign to roles in assembly and catalysis.

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