Will family studies return to prominence in human genetics and genomics? Rare variants and linkage analysis of complex traits

AbstractAny individual’s genome contains ∼4-5 million genetic variants that differ from reference, and understanding how these variants give rise to trait diversity and disease susceptibility is a central goal of human genetics1. A vast majority (96-99%) of an individual’s variants are common, though at a population level the overwhelming majority of variants are rare2–5. Because of their scarcity in an individual’s genome, rare variants that play important roles in complex traits are likely to have large functional effects6,7. Mutations that cause an exon to be skipped can have severe functional consequences on gene function, and many known disease-causing mutations reduce or eliminate exon recognition8. Here we explore the extent to which rare genetic variation in humans results in near complete loss of exon recognition. We developed a Multiplexed Functional Assay of Splicing using Sort-seq (MFASS) that allows us to measure exon inclusion in thousands of human exons and surrounding intronic sequence simultaneously. We assayed 27,733 extant variants in the Exome Aggregation Consortium (ExAC)9 within or adjacent to 2,339 human exons, and found that 3.8% (1,050) of the variants, almost all of which were extremely rare, led to large-effect defects in exon recognition. Importantly, we find that 83% of these splice-disrupting variants (SDVs) are located outside of canonical splice sites, are distributed evenly across distinct exonic and intronic regions, and are difficult to predict a priori. Our results indicate that loss of exon recognition is an important and underappreciated means by which rare variants exert large functional effects, and that MFASS enables their empirical assessment for splicing defects at scale.

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Evolution and Selection of Quantitative Traits

10.1093/oso/9780198830870.001.0001 ◽

2018 ◽

Cited By ~ 141

Author(s):

Bruce Walsh ◽

Michael Lynch

Keyword(s):

Mathematical Models ◽

Quantitative Genetics ◽

Complex Traits ◽

Evolutionary Biology ◽

Quantitative Traits ◽

Specific Gene ◽

Real World Data ◽

Holistic Treatment ◽

Genetics And Genomics ◽

Selection Of

Quantitative traits—be they morphological or physiological characters, aspects of behavior, or genome-level features such as the amount of RNA or protein expression for a specific gene—usually show considerable variation within and among populations. Quantitative genetics, also referred to as the genetics of complex traits, is the study of such characters and is based on mathematical models of evolution in which many genes influence the trait and in which non-genetic factors may also be important. Evolution and Selection of Quantitative Traits presents a holistic treatment of the subject, showing the interplay between theory and data with extensive discussions on statistical issues relating to the estimation of the biologically relevant parameters for these models. Quantitative genetics is viewed as the bridge between complex mathematical models of trait evolution and real-world data, and the authors have clearly framed their treatment as such. This is the second volume in a planned trilogy that summarizes the modern field of quantitative genetics, informed by empirical observations from wide-ranging fields (agriculture, evolution, ecology, and human biology) as well as population genetics, statistical theory, mathematical modeling, genetics, and genomics. Whilst volume 1 (1998) dealt with the genetics of such traits, the main focus of volume 2 is on their evolution, with a special emphasis on detecting selection (ranging from the use of genomic and historical data through to ecological field data) and examining its consequences. This extensive work of reference is suitable for graduate level students as well as professional researchers (both empiricists and theoreticians) in the fields of evolutionary biology, genetics, and genomics. It will also be of particular relevance and use to plant and animal breeders, human geneticists, and statisticians.

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A Primer of Population Genetics and Genomics

10.1093/oso/9780198862291.001.0001 ◽

2020 ◽

Author(s):

Daniel L. Hartl

Keyword(s):

Population Genetics ◽

Complex Traits ◽

Evolutionary Biology ◽

Knowledge Retention ◽

Learning By Doing ◽

Human Populations ◽

Gene Drive ◽

Molecular Population Genetics ◽

Genetics And Genomics ◽

And Mathematics

A Primer of Population Genetics and Genomics, 4th edition, has been completely revised and updated to provide a concise but comprehensive introduction to the basic concepts of population genetics and genomics. Recent textbooks have tended to focus on such specialized topics as the coalescent, molecular evolution, human population genetics, or genomics. This primer bucks that trend by encouraging a broader familiarity with, and understanding of, population genetics and genomics as a whole. The overview ranges from mating systems through the causes of evolution, molecular population genetics, and the genomics of complex traits. Interwoven are discussions of ancient DNA, gene drive, landscape genetics, identifying risk factors for complex diseases, the genomics of adaptation and speciation, and other active areas of research. The principles are illuminated by numerous examples from a wide variety of animals, plants, microbes, and human populations. The approach also emphasizes learning by doing, which in this case means solving numerical or conceptual problems. The rationale behind this is that the use of concepts in problem-solving lead to deeper understanding and longer knowledge retention. This accessible, introductory textbook is aimed principally at students of various levels and abilities (from senior undergraduate to postgraduate) as well as practising scientists in the fields of population genetics, ecology, evolutionary biology, computational biology, bioinformatics, biostatistics, physics, and mathematics.

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Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

Genetics in Medicine ◽

10.1038/s41436-021-01116-x ◽

2021 ◽

Author(s):

Suzanne C. E. H. Sallevelt ◽

Alexander P. A. Stegmann ◽

Bart de Koning ◽

Crool Velter ◽

Anja Steyls ◽

...

Keyword(s):

Autosomal Recessive ◽

Rare Variants ◽

Clinical Care ◽

Carrier Testing ◽

Carrier Status ◽

Routine Diagnostics ◽

Affected Offspring ◽

Pathogenic Variants ◽

Increased Risk ◽

Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

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Gene Hunting Approaches through the Combination of Linkage Analysis with Whole-Exome Sequencing in Mendelian Diseases: From Darwin to the Present Day

Public Health Genomics ◽

10.1159/000517102 ◽

2021 ◽

pp. 1-11

Author(s):

Seda Susgun ◽

Koray Kasan ◽

Emrah Yucesan

Keyword(s):

Linkage Analysis ◽

Rare Variants ◽

Parallel Implementation ◽

Association Studies ◽

Hereditary Diseases ◽

In Vivo Studies ◽

Consanguineous Marriages ◽

Gene Hunting

Background: In the context of medical genetics, gene hunting is the process of identifying and functionally characterizing genes or genetic variations that contribute to disease phenotypes. In this review, we would like to summarize gene hunting process in terms of historical aspects from Darwin to now. For this purpose, different approaches and recent developments will be detailed. Summary: Linkage analysis and association studies are the most common methods in use for explaining the genetic background of hereditary diseases and disorders. Although linkage analysis is a relatively old approach, it is still a powerful method to detect disease-causing rare variants using family-based data, particularly for consanguineous marriages. As is known that, consanguineous marriages or endogamy poses a social problem in developing countries, however, this same condition also provides a unique opportunity for scientists to identify and characterize pathogenic variants. The rapid advancements in sequencing technologies and their parallel implementation together with linkage analyses now allow us to identify the candidate variants related to diseases in a relatively short time. Furthermore, we can now go one step further and functionally characterize the causative variant through in vitro and in vivo studies and unveil the variant-phenotype relationships on a molecular level more robustly. Key Messages: Herein, we suggest that the combined analysis of linkage and exome analysis is a powerful and precise tool to diagnose clinically rare and recessively inherited conditions.

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Genetic Linkage Analysis: Simple Solutions for Complex Traits?

Alcoholism ◽

10.1007/978-1-4684-5946-3_17 ◽

1991 ◽

pp. 161-166

Author(s):

Luis A. Giuffra

Keyword(s):

Linkage Analysis ◽

Complex Traits ◽

Genetic Linkage ◽

Genetic Linkage Analysis

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Pairwise genetic interactions modulate lipid plasma levels and cellular uptake

10.1101/2020.10.29.360818 ◽

2020 ◽

Author(s):

Magdalena Zimon ◽

Yunfeng Huang ◽

Anthi Trasta ◽

Jimmy Z. Liu ◽

Chia-Yen Chen ◽

...

Keyword(s):

Complex Traits ◽

Drug Target ◽

Human Genetics ◽

Large Population ◽

Genetic Interactions ◽

Model Systems ◽

Lipid Lowering ◽

Gene Pairs ◽

Population Sizes ◽

The Uk

SUMMARYGenetic interactions (GIs), the joint impact of different genes or variants on a phenotype, are foundational to the genetic architecture of complex traits. However, identifying GIs through human genetics is challenging since it necessitates very large population sizes, while findings from model systems not always translate to humans. Here, we combined exome-sequencing and genotyping in the UK Biobank with combinatorial RNA-interference (coRNAi) screening to systematically test for pairwise GIs between 30 lipid GWAS genes. Gene-based protein-truncating variant (PTV) burden analyses from 240,970 exomes revealed additive GIs for APOB with PCSK9 and LPL, respectively. Both, genetics and coRNAi identified additive GIs for 12 additional gene pairs. Overlapping non-additive GIs were detected only for TOMM40 at the APOE locus with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate both, plasma and cellular lipid levels via additive and non-additive effects and nominates drug target pairs for improved lipid-lowering combination therapies.

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Clinical Impact of Rare Variants Associated with Inherited Channelopathies: A Five-Year Update

10.21203/rs.3.rs-369063/v1 ◽

2021 ◽

Author(s):

georgia sarquella ◽

Anna Fernandez ◽

sergi cesar ◽

elena arbelo ◽

monica coll ◽

...

Keyword(s):

Rare Variants ◽

Genetic Data ◽

Clinical Impact ◽

Clinical Translation ◽

Clinical Implications ◽

Frequency Data ◽

Unknown Significance ◽

Common Group ◽

Genetics And Genomics ◽

Proper Interpretation

Abstract A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified five years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included fourty-nine cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After five years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than five years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.

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