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bioRxiv2020

Modeling Parent-Specific Genetic Nurture in Families with Missing Parental Genotypes: Application to Birthweight and BMI

Disaggregation and estimation of genetic effects from offspring and parents has long been of interest to statistical geneticists. Recently, technical and methodological advances have made the genome-wide and loci-specific estimation of direct offspring and parental genetic nurture effects more possible. However, unbiased estimation using these methods requires datasets where both parents and at least one child have been genotyped, which are relatively scarce. Our group has recently developed a method and accompanying software (IMPISH; Hwang et al., 2020) which is able to impute missing parental genotypes from observed data on sibships and estimate their effects on an offspring phenotype conditional on the effects of genetic transmission. However, this method is unable to disentangle maternal and paternal effects, which may differ in magnitude and direction. Here, we introduce an extension to the original IMPISH routine which takes advantage of all available nuclear families to impute parent-specific missing genotypes and obtain asymptotically unbiased estimates of genetic effects on offspring phenotypes. We apply this this method to data from related individuals in the UK Biobank, showing concordance with previous estimates of maternal genetic effects on offspring birthweight. We also conduct the first GWAS jointly estimating offspring-, maternal-, and paternal-specific genetic effects on body mass index.

genetics↗

bioRxiv2020

Fine-scale population structure confounds genetic risk scores in the ascertainment population

Polygenic risk scores, or PRS, are a tool to estimate individuals liabilities to a disease or trait measurement based solely on genetic information. One commonly discussed potential use is in the clinic to identify people who are at greater risk of developing a disease. In this paper, we compare three PRS models that incorporate a large number of genetic markers for coronary artery disease (CAD). In the UK Biobank, the cohort which was used at some point in the creation or validation of each score, we calculated the association between CAD, the scores, and population structure for the white British subset. After adjusting for geographic and socioeconomic factors, CAD was not associated with the first principal components of genetic diversity, which reflect fine-scale population structure. In contrast, all three scores were confounded by these genetic components, highlighting that PRS may be influenced by genetic factors not directly causal for CAD, thereby raising concerns about their biases in clinical application.Furthermore, we investigated the differences in risk stratification using four different UK Biobank assessment centers as separate cohorts, and tested how missing genetic data affected risk stratification through simulation. We show that missing data impact classification for extreme individuals for high- and low-risk, and quantiles of risk are sensitive to individual-level genotype missingness. Distributions of scores varied between assessment centers, revealing that thresholding based on quantiles can be problematic for consistency across centers and populations. Based on these results, we discuss potential avenues of improvements of PRS methodologies for usage in clinical practice.

genetics↗

bioRxiv2020

The genotypic and genetic diversity of enset (Ensete ventricosum) landraces used in traditional medicine is similar to the diversity found in starchy landraces

BackgroundEnset (Ensete ventricosum) is a multipurpose crop extensively cultivated in southern and southwestern Ethiopia for human food, animal feed and fiber. It contributes to the food security and rural livelihoods of 20 million people. Several distinct enset landraces are cultivated for their uses in traditional medicine. Socio-economic changes and the loss of indigenous knowledge might lead to the decline of important medicinal landraces and their associated genetic diversity. However, it is currently unknown whether medicinal landraces are genetically differentiated from other landraces. Here, we characterize the genetic diversity of medicinal enset landraces to support effective conservation and utilization of their diversity ResultsWe evaluated the genetic diversity of 51 enset landraces of which 38 have reported medicinal value. A total of 38 alleles were detected across the 15 SSR loci. AMOVA revealed that 97.6% of the total genetic variation is among individual with an FST of 0.024 between medicinal and non-medicinal landraces. A neighbor-joining tree showed four separate clusters with no correlation to the use values of the landraces. Principal coordinate analysis also confirmed the absence of distinct clustering between the groups, showing low differentiation among landraces used in traditional medicine and those having other use values. ConclusionWe found that enset landraces were clustered irrespective of their use value, showing no evidence for genetic differentiation between enset grown for medicinal uses and non-medicinal landraces. This suggests that enset medicinal properties may be restricted to a more limited number of genotypes, a product of interaction with the environment or management practice, or partly misreported. The study provide baseline information that promotes further investigations in exploiting the medicinal value of these specific landraces

genetics↗

bioRxiv2020

Using Genetic Information to Improve the Prediction of Individual Food Choice: A Case Study of Alcoholic Beverages

Individual food choices and consumption are closely relating to ones diet, nutrition, and health. Using the case of alcoholic beverages, this study extends the random-utility framework by incorporating genetic information into consumer demand models, and demonstrates the significant impact of genetic factors on individual food choice decisions in a novel way. Integrating individual-level responses of discrete choice experiments (DCE), genotyping data, and socioeconomic/demographic characteristics of 484 participants collected from face-to-face interviews in mainland China, we employ a machine learning-based classification (MLC) approach to identify and predict individual choices. We show that genetic factors are critical to explaining variations in both general drinking behavior and choices of particular products. We systematically compared the performance of traditional discrete choice models and MLC models without and with genetic factors. The MLC predictive model with both socio-demographic and genetic features yields the highest accuracy of 74.7% and AUC-ROC of 0.85. Our findings warrant further economic studies of human behaviors with the integration of genetic data.

genetics↗

bioRxiv2021

Genetic Diversity of Dianthus Plants Revealed by SRAP Markers

Dianthus is a valuable genetic resource for flower breeding. However, study on the genetic similarity of Dianthus plants is rare. In this work, 20 pairs of SRAP markers were used to analyze genetic diversity of 44 Dianthus plants, including 13 lines of wild Dianthus chinensis L., 7 lines of wild Dianthus superbus L. and 24 commercial varieties including Dianthus caryophyllus L., Dianthus plumarius L. and Dianthus barbatus L.. Results showed that precise interspecific and intraspecific genetic diversity was provided in Dianthus plants by using 20 pairs of SRAP molecular markers. The interspecific genetic diversity of Dianthus plants was much abundant and the intraspecific genetic difference of wild Dianthus species was related to their geographical distribution and habitats. In this work, theoretical basis and technical support were provided for crossbreeding and molecular mechanism research of Dianthus plants.

genetics↗

bioRxiv2021

ATP-dependent Clp protease subunit C1, HvClpC1, is a strong candidate gene for barley variegation mutant luteostrians as revealed by genetic mapping and genomic re-sequencing

Implementation of next-generation sequencing in forward genetic screens greatly accelerated gene discovery in species with larger genomes, including many crop plants. In barley, extensive mutant collections are available, however, the causative mutations for many of the genes remains largely unknown. Here we demonstrate how a combination of low-resolution genetic mapping, whole-genome resequencing and comparative functional analyses provides a promising path towards candidate identification of genes involved in plastid biology and / or photosynthesis, even if genes are located in recombination poor regions of the genome. As a proof of concept, we simulated the prediction of a candidate gene for the recently cloned variegation mutant albostrians (HvAST / HvCMF7) and adopted the approach for suggesting HvClpC1 as candidate gene for the yellow-green variegation mutant luteostrians. Author SummaryForward genetics is an approach of identifying a causal gene for a mutant phenotype and has proven to be a powerful tool for dissecting the genetic control of biological processes in many species. A large number of barley mutants was generated in the 1940s to 1970s when mutation breeding programs flourished. Genetic dissection of the causative mutations responsible for the phenotype, however, lagged far behind, limited by lack of molecular markers and high-throughput genotyping platforms. Next-generation sequencing technologies have revolutionized genomics, facilitating the process of identifying mutations underlying a phenotype of interest. Multiple mapping-by-sequencing or cloning-by-sequencing strategies were established towards fast gene discovery. In this study, we used mapping-by-sequencing to identify candidate genes within coarsely delimited genetic intervals, for two variegation mutants in barley - luteostrians and albostrians. After testing the approach using the example of the previously cloned albostrians gene HvAST, the gene HvClpC1 could be delimited as candidate gene for luteostrians. The mapping-by-sequencing strategy implemented here is generally suited for surveying barley mutant collections for phenotypes affecting fundamental processes of plant morphology, physiology and development.

genetics↗

bioRxiv2021

High-resolution genetic mapping reveals cis-regulatory and copy number variation in loci associated with cytochrome P450-mediated detoxification in a generalist arthropod pest

Chemical control strategies are driving the evolution of pesticide resistance in pest populations. Understanding the genetic mechanisms of these evolutionary processes is of crucial importance to develop sustainable resistance management strategies. The acaricide pyflubumide is one of the most recently developed mitochondrial complex II inhibitors with a new mode of action that specifically targets spider mite pests. In this study, we characterize the molecular basis of pyflubumide resistance in a highly resistant population of the spider mite Tetranychus urticae. Classical genetic crosses indicated that pyflubumide resistance was incompletely recessive and controlled by more than one gene. To identify resistance loci, we crossed the resistant population to a highly susceptible T. urticae inbred strain and propagated resulting populations with and without pyflubumide exposure for multiple generations in an experimental evolution set-up. High-resolution genetic mapping by a bulked segregant analysis approach led to the identification of three quantitative trait loci (QTL) linked to pyflubumide resistance. Two QTLs were found on the first chromosome and centered on the cytochrome P450 CYP392A16 and a cluster of CYP392E6-8 genes. Comparative transcriptomics revealed a consistent overexpression of CYP392A16 and CYP392E8 in the experimental populations that were selected for pyflubumide resistance. We further corroborated the involvement of CYP392A16 in resistance by in vitro functional expression and metabolism studies. Collectively, these experiments uncovered that CYP392A16 N-demethylates the toxic carboxamide form of pyflubumide to a non-toxic compound. A third QTL coincided with cytochrome P450 reductase (CPR), a vital component of cytochrome P450 metabolism. We show here that the resistant population harbors three gene copies of CPR and that this copy number variation is associated with higher mRNA abundance. Together, we provide evidence for detoxification of pyflubumide by cytochrome P450s that is likely synergized by gene amplification of CPR. Author summaryOur understanding of the causal genetic variants that drive the evolution of quantitative traits, such as polygenic pesticide resistance, remains very limited. Here, we followed a high-resolution genetic mapping approach to localize the genetic variants that cause pyflubumide resistance in the two-spotted spider mite Tetranychus urticae. Three well-supported QTL were uncovered and pointed towards a major role for cytochrome P450-mediated detoxification. Cis-regulatory variation for cytochrome P450s was observed, and in vitro cytochrome P450 experiments showed that pyflubumide was metabolized into a non-toxic derivate. A third QTL centered on cytochrome P450 reductase (CPR), which is required for cytochrome P450 activity, and is amplified in pyflubumide resistant populations. Our results indicate that pyflubumide resistance is mediated by cytochrome P450 detoxification that is enhanced by gene amplification at the CPR locus. Data availabilitySequence data has been deposited at the Sequence Read Archive (PRJNA596790). Phenotypic quantification data is available at Supplementary Data S1.

genetics↗

bioRxiv2021

Genetic resistance to yellow rust infection of the wheat ear is controlled by genes controlling foliar resistance and flowering time

Yellow rust (YR), or stripe rust, is a fungal infection of wheat (Triticum aestivum L.) caused by the pathogen Puccinia striiformis Westend f. sp. tritici (Pst). While much research has focused on YR infection of wheat leaves, we are not aware of reports investigating the genetic control of YR resistance in other wheat structures, such as the ears. Here we use an eight-founder population to undertake genetic analysis of glume YR infection in wheat ears. Five quantitative trait loci (QTL) were identified, each explaining between ~3-7% of the phenotypic variation. Of these, three (QYrg.niab-2D.2, QYrg.niab-4D.1 and QYrg.niab-5A.1) co-located with QTL for leaf YR resistance previously identified in the same population, with evidence suggesting QYrg.niab-5A.1 may correspond to the adult plant resistance locus Yr34 which originates from T. monococcum ssp. monococcum and that resistance at QYrg.niab-2D.2 may be conferred by chromosomal introgression from a wheat relative. Additional leaf YR resistance QTL previously identified in the population were not detected as controlling glume resistance, with the remaining two glume YR QTL linked to genetic loci controlling flowering time. The first of these, QYrg.niab-2D.1, mapped to the major flowering time locus Photoperiod-D1 (Ppd-D1), with the early-flowering allele from the MAGIC founder Soissons conferring reduced glume YR resistance. The second, QYrg.niab-4A.1, was identified in one trial only, and was located close to a flowering time QTL. This indicates earlier flowering results in increased glume YR susceptibility, likely due to exposure of tissues during environmental conditions more favourable for Pst infection. Collectively, our results provide first insights into the genetic control of YR resistance in glumes, controlled by subsets of QTL for leaf YR resistance and flowering time. This work provides specific genetic targets for the control of YR resistance in both the leaves and the glumes, and may be especially relevant in Pst-prone agricultural environments where earlier flowering is favoured. Core ideasO_LIPuccinia striiformis Westend f. sp. tritici (Pst) causes yellow rust (YR) in wheat leaves and ears. C_LIO_LIWe present the first reports for the genetic control of YR on the wheat ear. C_LIO_LIEar YR infection is controlled by subsets of QTL controlling leaf resistance and flowering time. C_LIO_LIThe findings are relevant to wheat breeding for Pst-prone environments. C_LI

genetics↗

bioRxiv2021

Stabilizing genetically unstable simple sequence repeats in the Campylobacter jejuni genome by multiplex genome editing: a reliable approach for delineating multiple phase-variable genes

Hypermutability of simple sequence repeats (SSR) through DNA slippage is a major mechanism of phase variation in Campylobacter jejuni. The presence of multiple SSR-mediated phase-variable genes encoding enzymes that modify surface structures, including capsular polysaccharide (CPS) and lipooligosaccharide (LOS), generates high levels of structural variants within bacterial populations, thereby promoting adaptation to selective pressures in host environments. Therefore, the phenotypic diversity generated by phase variation can limit the reproducibility of results with C. jejuni; therefore, researchers need to genetically control the mutability of multiple SSRs. Here, we show that natural "cotransformation" is an effective method for C. jejuni genome editing. Cotransformation is a trait of naturally competent bacteria that causes uptake and integration of multiple different DNA fragments, which has been recently adapted to multiplex genome editing by natural transformation (MuGENT), a method for introducing multiple scarless mutations into the genomes of these bacteria. We found that the cotransformation frequencies of antibiotic resistance gene-marked DNA fragments and unmarked DNA fragments reached ~40% in C. jejuni. To examine the feasibility of MuGENT in C. jejuni, we "locked" either different polyG SSR tracts in strain NCTC11168 (which are located in the biosynthetic CPS and LOS gene clusters) into either the ON or OFF configurations by interrupting the continuous runs of G residues without changing the encoded amino acids. This approach, termed "MuGENT-SSR," enabled the generation of all eight edits within 2 weeks and the identification of a phase-locked strain with a highly stable type of Penner serotyping, a CPS-based serotyping scheme. Furthermore, extensive genome editing of this strain by MuGENT-SSR identified a phase-variable gene that determines the Penner serotype of NCTC11168. Thus, MuGENT-SSR provides a platform for genetic and phenotypic engineering of genetically unstable C. jejuni, making it a reliable approach for elucidating the mechanisms underlying phase-variable expression of specific phenotypes. Author summaryCampylobacter jejuni is the leading bacterial cause of food-borne gastroenteritis in developed countries and occasionally progresses to the autoimmune disease Guillain-Barre syndrome. The genetically and phenotypically unstable features of this bacterial species limit research and development efforts. A relatively large number of hypermutable simple sequence repeat (SSR) tracts in the C. jejuni genome markedly decreases its phenotypic stability through reversible changes in the ON or OFF expression states of the genes in which they reside, a phenomenon called phase variation. Thus, controlling SSR-mediated phase variation can be important for achieving stable and reproducible research on C. jejuni. In this study, we developed a feasible and effective approach to genetically manipulate multiple SSR tracts in the C. jejuni genome using natural cotransformation, a trait of naturally transformable bacterial species that causes the uptake and integration of multiple different DNA molecules. This approach will greatly help to improve the genetic and phenotypic stability of C. jejuni to enable diverse applications in research and development.

genetics↗

bioRxiv2021

Reviewing the consequences of genetic purging on the success of rescue programs

Genetic rescue is increasingly considered a promising and underused conservation strategy to reduce inbreeding depression and restore genetic diversity in endangered populations, but the empirical evidence supporting its application is limited to a few generations. Here we discuss on the light of theory the role of inbreeding depression arising from partially recessive deleterious mutations and of genetic purging as main determinants of the medium to long-term success of rescue programs. This role depends on two main predictions: (1) The inbreeding load hidden in populations with a long stable demography increases with the effective population size; and (2) After a population shrinks, purging tends to remove its (partially) recessive deleterious alleles, a process that is slower but more efficient for large populations than for small ones. We also carry out computer simulations to investigate the impact of genetic purging on the medium to long term success of genetic rescue programs. For some scenarios, it is found that hybrid vigor followed by purging will lead to sustained successful rescue. However, there may be specific situations where the recipient population is so small that it cannot purge the inbreeding load introduced by migrants, which would lead to increased fitness inbreeding depression and extinction risk in the medium to long term. In such cases, the risk is expected to be higher if migrants came from a large non-purged population with high inbreeding load, particularly after the accumulation of the stochastic effects ascribed to repeated occasional migration events. Therefore, under the specific deleterious recessive mutation model considered, we conclude that additional caution should be taken in rescue programs. Unless the endangered population harbors some distinctive genetic singularity whose conservation is a main concern, restoration by continuous stable gene flow should be considered, whenever feasible, as it reduces the extinction risk compared to repeated occasional migration and can also allow recolonization events.

genetics↗

bioRxiv2021

Contribution of 3D genome topological domains to genetic risk of cancers

Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases display such a preferential location of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that TAD border enrichment in risk loci differ between cancers and non-cancer diseases. Different TAD border enrichments are observed in embryonic stem cells and differentiated cells, which agrees with an evolution along embryogenesis of the 3D genome organization into topological domains. Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization. Author summaryGenome-wide association studies comparing patients and healthy subjects have evidenced correlations between diseases and the presence of pointwise genetic variations known as single-nucleotide polymorphisms (SNPs). We exploit and extend this statistical analysis by investigating the location of risk loci, i.e. disease-associated SNPs, with respect to the 3D organization of the genome into spatially-insulated domains, the topologically-associating domains (TADs). We show that for certain diseases, mostly cancers, their associated risk loci are preferentially located in the borders of these topological domains. The predominance of cancers among these diseases is confirmed and even enhanced when considering only intergenic SNPs. A different enrichment behavior is observed in embryonic stem cells and derived cell lines at an early developmental stage, presumably due to the not fully mature TAD structure in these cells. Overall, our results show that genome variations in specific TAD borders may increase the risk of developing certain diseases, especially cancers. Our work underlines the importance of considering the genetic risk loci within their 3D genomic context, and suggests a role of 3D genome partitioning into topological domains in the genetic risk which differs between cancers and non-cancer diseases.

genetics↗

bioRxiv2021

Genetic diversity of local and introduced cassava germplasm in Burundi using DArTseq molecular analyses

In Burundi, most of small-scale farmers still grow traditional cassava landraces that are adapted to local conditions and have been selected for consumer preferred attributes. They tend to be susceptible, in varying degrees, to devastating cassava viral diseases such as Cassava Brown Steak Disease (CBSD) and Cassava Mosaic Disease (CMD) with production annual losses of US$1 billion annually. For long term resistance to the disease, several breeding strategies have been proposed. A sound basis for a breeding program is to understand the genetic diversity of both landraces and elite introduced breeding cultivars. This will also assist in efforts to conserve landraces ahead of the broad distribution of improved varieties which have the possibility of replacing landraces. Our study aimed at determining the genetic diversity and relationships of local landraces and introduced elite germplasm using morphological and simple nucleotide polymorphism (SNP) markers as well as identifying a core set of germplasm from the local varieties to be used in the cassava breeding program. A total of 118 cultivars were characterized for morphological trait variation based on leaf, stem and root traits, and genetic variation using SNP markers. Results of morphological characterization based on Wards Method revealed three main clusters and five accessions sharing similar characteristics. Molecular characterization identified over 18,000 SNPs and six main clusters and three pairs of duplicates which should be pooled together as one cultivar to avoid redundancy. Results of population genetic analysis showed low genetic distance between populations and between local landraces and elite germplasm. Accessions that shared similar morphological traits were divergent at the molecular level indicating that clustering using morphological traits was inconsistent. Despite the variabilities found within the collection, it was observed that cassava germplasm in Burundi have a narrow genetic base.

genetics↗

bioRxiv2021

A genealogical estimate of genetic relationships

The application of genetic relationships among individuals, characterized by a genetic relationship matrix (GRM), has far-reaching effects in human genetics. However, the current standard to calculate the GRM generally does not take advantage of linkage information and does not reflect the underlying genealogical history of the study sample. Here, we propose a coalescent-informed framework to infer the expected relatedness between pairs of individuals given an ancestral recombination graph (ARG) of the sample. Through extensive simulations we show that the eGRM is an unbiased estimate of latent pairwise genome-wide relatedness and is robust when computed using genealogies inferred from incomplete genetic data. As a result, the eGRM better captures the structure of a population than the canonical GRM, even when using the same genetic information. More importantly, our framework allows a principled approach to estimate the eGRM at different time depths of the ARG, thereby revealing the time-varying nature of population structure in a sample. When applied to genotyping data from a population sample from Northern and Eastern Finland, we find that clustering analysis using the eGRM reveals population structure driven by subpopulations that would not be apparent using the canonical GRM, and that temporally the population model is consistent with recent divergence and expansion. Taken together, our proposed eGRM provides a robust tree-centric estimate of relatedness with wide application to genetic studies.

genetics↗

bioRxiv2021

History-Dependent Physiological Adaptation to Lethal Genetic Modification under Antibiotic Exposure

Genetic modifications, such as gene deletion and mutations, could lead to significant changes in physiological states or even cell death. Bacterial cells can adapt to diverse external stresses, such as antibiotic exposure, but can they also adapt to detrimental genetic modification? To address this issue, we visualized the response of individual Escherichia coli cells to deletion of the antibiotic resistance gene under chloramphenicol (Cp) exposure, combining the light-inducible genetic recombination and microfluidic long-term single-cell tracking. We found that a significant fraction ([~] 40%) of resistance-gene-deleted cells demonstrated a gradual restoration of growth and stably proliferated under continuous Cp exposure without additional mutations. Such physiological adaptation to genetic modification was not observed when the deletion was introduced in 10 h or more advance before Cp exposure. Resistance gene deletion under Cp exposure disrupted the stoichiometric balance of ribosomal large and small subunit proteins (RplS and RpsB). However, the balance was gradually recovered in the cell lineages with restored growth. These results demonstrate that bacterial cells can adapt even to lethal genetic modifications by plastically gaining physiological resistance. However, the access to the resistance states is limited by the environmental histories and the timings of genetic modification.

genetics↗

bioRxiv2022

Genetic modifiers of Cep290-mediated retinal degeneration

Mutations in CEP290 cause up to 30% of cases of Leber congenital amaurosis (LCA), a severe childhood blindness resulting from abnormalities in the photoreceptor connecting cilia that lead to rapid retinal degeneration. Like many genetic diseases, CEP290-LCA has considerable variable expressivity, indicating the presence of other factors that influence phenotypic outcome. Here, we have undertaken a phenotype-driven approach in mice to identify genetic modifiers of CEP290-mediated retinal degeneration through backcrosses and intercrosses between BXD24-Cep290rd16 mice and the genetically distinct inbred CAST strain to introduce genetic variation. Optical coherence tomography was used to quantitatively measure retinal thickness as a surrogate indication of photoreceptor degeneration in the resulting rd16-mutant mice. It was readily apparent that CEP290-mediated retinal degeneration in the resulting mice is sensitive to genetic background, with some mice exhibiting relatively thick laminated retinas and others having thin retinas with advanced disease. Quantitative trait locus (QTL) analysis identified multiple genomic loci capable of influencing the retinal degeneration phenotype in Cep290-mutant mice that together account for 71.7% of the phenotypic variation in retinal thickness observed in our population. Following the QTL analysis, two suppressor loci were studied in detail through a combination of physical and molecular approaches to narrow the critical region for each QTL and identify the probable causative genetic variations.

genetics↗

bioRxiv2022

Tracing genetic connections of ancient Hungarians to the 6-14th century populations of the Volga-Ural region

Most of the early Hungarian tribes originated from the Volga-Kama and South-Ural regions, where they were composed of a mixed population based on historical, philological, and archaeological data. We present here the uniparental genetic makeup of the medieval era of these regions that served as a melting pot for ethnic groups with different linguistic and historical backgrounds. Representing diverse cultural contexts, the new genetic data originates from ancient proto-Ob-Ugric people from Western Siberia (6th-13th century), the pre-Conquest period, and subsisting Hungarians from the Volga-Ural region (6th-14th century) and their neighbours. By examining the eastern archaeology traits of Hungarian prehistory, we also study their genetic composition and origin in an interdisciplinary framework. We analysed 110 deep-sequenced mitogenomes and 42 Y-chromosome haplotypes from 18 archaeological sites in Russia. The results support the studied groups genetic relationships regardless of geographical distances, suggesting large-scale mobility. We detected long-lasting genetic connections between the sites representing the Kushnarenkovo and Chiyalik cultures and the Carpathian Basin Hungarians and confirmed the Uralic transmission of several East-Eurasian uniparental lineages in their genepool. Based on phylogenetics, we demonstrate and model the connections and splits of the studied Volga-Ural and conqueror groups. Early Hungarians and their alliances conquered the Carpathian Basin around 890 AD. Re-analysis of the Hungarian conquerors maternal genepool reveals numerous surviving maternal relationships in both sexes; therefore, we conclude that men and women came to the Carpathian Basin together, and although they were subsequently genetically fused into the local population, certain eastern lineages survived for centuries.

genetics↗

bioRxiv2022

The Genetics of Participation: Method and Analysis

Participation in a genetic study likely has a genetic component. Identifying such component is difficult as we cannot compare genetic information of participants with non-participants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than non-participants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. A polygenic score constructed from that analysis, in non-overlapping samples, is associated with educational attainment (P = 2.1 x 10-52), body mass index (P = 1.5 x 10-19), and participation in a dietary study (P = 6.9 x 10-21). Further analysis shows that inclination to participate is a behavioural trait in its own right, and not simply a consequence of other established phenotypes. Understanding the basis of this trait is important for data analyses and the design of future surveys, genetic or otherwise.

genetics↗

bioRxiv2022

Genetic affinities and adaptation of the South West coast populations of India

Evolutionary event has not only transformed the genetic structure of human populations but also associated with social and cultural transformation. South Asian populations were formed as a result of such evolutionary events of migration and admixture of genetically and culturally distinct groups. Most of the genetic studies pointed to large-scale admixture event between Ancestral North Indian (ANI) and Ancestral South Indian (ASI) groups, also additional layers of recent admixture. In the present study we have analyzed 213 individuals inhabited in South West coast India with traditional warriors and feudal lord status and historically associated with recent migrations events and possible admixture with Indo-Scythians, Saka, Huns and Kushans, whose genetic links are still missing. Analysis of autosomal SNP markers suggests that these groups possibly derived their ancestry from some groups of North West India having additional Middle Eastern genetic component and also their separation history suggests very early separation from North West Indian and Gangetic plain Indo-Europeans during late bronze or Iron age, most probably following central India and Godavari basin to South West coast. Higher distribution of west Eurasian mitochondrial haplogroups also points to admixture through maternal lineage. Selection screen using genome wide genealogy approach revealed genetic signatures related to their long-term coastal food habits. Thus, our study suggests that the South West coastal groups with traditional warriors and feudal lords status are of a distinct lineage compared to Dravidian and Gangetic plain Indo-Europeans and are remnants of very early migrations from North West India following Godavari basin to Karnataka and Kerala.

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