Mendelian Variation Research Articles

The fifth international hackathon for developing computational cloud-based tools and resources for pan-structural variation and genomics

Background The goal of the Fifth Annual Baylor College of Medicine & DNAnexus Structural Variation Hackathon was to push forward the research on structural variants (SVs) by rapidly developing and deploying open-source software. The event took place in-person and virtually in August 2023, when 49 scientists from 14 countries and 8 U.S. states collaboratively worked on projects to address critical gaps in the field of genomics. The hackathon projects concentrated on developing bioinformatic workflows for the following challenges: RNA transcriptome comparison, simulation of mosaic variations, metagenomics, Mendelian variation, SVs in plant genomics, and assembly vs. mapping SV calling comparisons. Methods As a starting point we used publicly available data from state-of-the-art long- and short-read sequencing technologies. The workflows developed during the hackathon incorporated open-source software, as well as scripts written using Bash and Python. Moreover, we leveraged the advantages of Docker and Snakemake for workflow automation. Results The results of the hackathon consists of six prototype bioinformatic workflows that use open-source software for SV research. We made the workflows scalable and modular for usability and reproducibility. Furthermore, we tested the workflows on example public data to show that the workflows can work. The code and the data produced during the event have been made publicly available on GitHub (https://github.com/collaborativebioinformatics) to reproduce and built upon in the future. Conclusions The following sections describe the motivation, lessons learned, and software produced by teams during the hackathon. Here, we describe in detail the objectives, value propositions, implementation, and use cases for our workflows. In summary, the article reports the advancements in the development of software for SV detection made during the hackathon.

Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension.

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 (SYNE1), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1, we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future.

Promise and Peril of Population Genomics for the Development of Genome-First Approaches in Mendelian Cardiovascular Disease.

The rich tradition of cardiovascular genomics has placed the field in prime position to extend our knowledge toward a genome-first approach to diagnosis and therapy. Population-scale genomic data has enabled exponential improvements in our ability to adjudicate variant pathogenicity based on allele rarity, and there has been a significant effort to employ these sizeable data in the investigation of rare disease. Certainly, population genomics data has great potential to aid the development of a genome-first approach to Mendelian cardiovascular disease, but its use in the clinical and investigative decision making is limited by the characteristics of the populations studied, and the evolutionary constraints on human Mendelian variation. To truly empower clinicians and patients, the successful implementation of a genome-first approach to rare cardiovascular disease will require the nuanced incorporation of population-based discovery with detailed investigation of rare disease cohorts and prospective variant evaluation.

A Nondegenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

India’s Self, Cross & Often Cross Pollinated Crops ?n The Global Crop Production: Mendelian variation Perspectives

Global agricultural growth has been slowing down. Crop production constitutes lion share of agricultural output. Empirical studies show that over the 40 years, crops growth rates in terms of yield gains and total production has been impressive but not substantial. This is mirroring in general in most of the developing countries and in India in particular. Crop plants originated from wild species through Mendelian variation, inter-specific hybridization or polyploidy. Genetic diversity plays an important role in crop improvement because hybridization between lines of diverse origin generally displays a greater heterosis than between, closely related strains. Infect, genetic diversity is more in cross-pollinated crops compared to self-pollinated crops. Until now, researchers and public are dealing with the agricultural production performance under cereals, pulses, oilseeds, fibber crops and so on but there is no (limited) study analyzed based on Mendelian variation. So this study uses new way of analyzes based on Mendelian variation perspective to study the production performance and growth trends of crops under self, cross and often cross-pollinated crops. The present paper is an attempt to examine critically the compound growth rates of area, production and productivity during distinct epochs in the agricultural development of India. Further, focus on the performance status of India’s major crops vis-a-vis the top three crop productivity nations of the world with special reference to self, cross and often cross-pollinated crops for the period of 1950-51 to 2011-12. Essentially, such a comparison will provide insights regarding the magnitude of the yield-gap that countries having low productivity need to bridge. A comparison of India with other nations reveals that India is second in the rice, wheat and groundnut production. The production differences between India and those nations are substantial in cross and often cross-pollinated crops compare to self-pollinated crops. However, the productivity differences between India and high productivity countries are more in cross-pollinated crops followed by self and often cross-pollinated crops. India needs to explore comparative yield advantages in cross-pollinated crops. Rice and wheat are the two principal crops grown in India. Though cross pollinated and often cross pollinated crops such as maize, sugarcane, cotton and tobacco hold promise for the future, the incessant area expansion under rice and wheat have relegated these crops to the background. In India, compound growth rates reflect that the pivot of green revolution as wheat. This is reflected by the crop growth rate of 5.65% during green revolution period. All through wheat productivity increased at increasing rates of 1.27%, 2.67% and 2.97% indicates technological breakthroughs in wheat production. Similarly, cotton productivity also increased at increasing rates of 2.04%, 2.54%, and 3.75%. To conclude, among self-pollinated crops; India stands second in paddy, wheat, groundnut and first in jute production. But in terms of productivity India trails behind higher productive countries. This calls for steps to enhance productivity. Further, scientists should give more emphasis on cross-pollinated crops. Bureaus of plant genetic resources must preserve and take steps to enhance genetic diversity of these crops. Planners and policy makers must have vigilance in land allocation and price fixation based on Mendelian variation of crops.

Lack of congruence between genetic and morphological stock structure of the southern African anglerfishLophius vomerinus

Meristic and morphometric variation and isozyme population markers were used to study the geographic stock structure of the southern African anglerfish Lophius vomerinus. Analysis of variance (ANOVA) revealed that the numbers of vertebrae and left pectoral fin rays differed significantly among areas. ANOVA of size-free estimates of morphometric variables showed that the length of the second dorsal fin spine, the head width and the snout width differed significantly among areas. A size-free principal component analysis (PCA) revealed that head characters and dorsal spine lengths covaried. A discriminant function based on meristic and morphometric characters correctly classified 36 and 51 per cent of the individuals respectively. A total of 24 protein-encoding loci was examined for Mendelian variation with starch-gel electrophoresis. Average heterozygosity (H) was 12,6 per cent, larger than that for most other marine fishes. There were no significant differences in allele-frequency among areas for nine polymorphic loci. A gene-diversity analysis showed that most of the genetic variation was contained within areas (99,62%), and that only a fraction of the total (0,38%) could be attributable to geographic differences among locations. Combining the data shows that the slight morphological differentiation among areas does not have a genetic basis. A conservative management policy, however, would be to set separate harvesting quotas for Namibia, for the South African west coast and for the South African south coast.

Biochemical Population Genetics of Pacific Halibut (Hippoglossus stenolepis) and Comparison with Atlantic Halibut (H.hippoglossus)

The gene products of 35 protein-coding loci were examined for Mendelian variation in three samples of Pacific halibut (Hippoglossus stenolepis) and one sample of Atlantic halibut (H. hippoglossus). Contingency table analyses of allelic frequencies for five polymorphic loci revealed no significant frequency differences between the Bering Sea and the Gulf of Alaska but detected significant Ada-2 frequency differences between these regions and Japan. Average genetic distance between the samples of Pacific halibut was 0.0002 ± 0.0007, and gene diversity analyses showed that 98.7% of the total genetic variation was contained within populations, 0.4% was due to differences between the Bering Sea and the Gulf of Alaska, and 0.9% was due to differences between these regions and Japan. These results are consistent with a larval drift, juvenile migration model of population genetic structure where not all juveniles home to their natal areas. Nei's genetic distance between Pacific and Atlantic halibut was 0.162 ± 0.073, and the molecular clock hypothesis suggests that these species became reproductively isolated from one another in the Pliocene between 1.7 and 4.5 million years ago.

Natural Selection and Mendelian Variation

Proceedings of the London Mathematical SocietyVolume s2-28, Issue 1 p. 1-45 Papers Natural Selection and Mendelian Variation H. T. J. Norton, H. T. J. NortonSearch for more papers by this author H. T. J. Norton, H. T. J. NortonSearch for more papers by this author First published: 1928 https://doi.org/10.1112/plms/s2-28.1.1Citations: 42AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volumes2-28, Issue11928Pages 1-45 RelatedInformation

Mendelian Variation in the Paracolon Mutabile Colon Group and the application of Mendel's Principles to the Theory of Acquired Virulence

It is the thesis of this paper that Mendel's principle of varitaion, formed from the study of the genetics of higher plants and animals, can be applied also to bacteria, and that acquired virulence in bacteria is the result of Mendelian variation.