Mendelian disease genomic research has undergone a massive transformation over the last decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. Over the last 10 years, the NIH-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Mendelian genomic research extends beyond generating lists of gene-phenotype relationships, it includes developing tools, training the larger community to use these tools and approaches, and facilitating collaboration through data sharing. Thus, the CMGs have also focused on creating resources, tools, and training for the larger community to foster the understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into AnVIL (NHGRI’s Genomic Data Science Analysis, Visualization, and Informatics Lab-Space), sharing candidate genes through Matchmaker Exchange (MME) and the CMG website, and sharing variants in Geno2MP and VariantMatcher. The research genomics output remains exploratory with evidence that thousands of disease genes, in which variant alleles contribute to disease, remain undiscovered, and many patients with rare disease remain molecularly undiagnosed. Strengthening communication between research and clinical labs, continued development and sharing of knowledge and tools required for solving previously unsolved cases, and improving access to data sets, including high-quality metadata, are all required to continue to advance Mendelian genomics research and continue to leverage the Human Genome Project for basic biomedical science research and clinical utility.

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Centers for Mendelian Genomics: A decade of facilitating gene discovery

Variability of cross-tissue X-chromosome inactivation characterizes timing of human embryonic lineage specification events.

Every cell in the human body inherits a copy of the same genetic information. The three billion base pairs of DNA in the human genome, and the roughly 50 000 coding and non-coding genes they contain, must thus encode all the complexity of human development and cell and tissue type diversity. Differences in gene regulation, or the modulation of gene expression, enable individual cells to interpret the genome differently to carry out their specific functions. Here we discuss recent and ongoing efforts to build gene regulatory maps, which aim to characterize all sequences in a genome for their roles in regulating gene expression. Many researchers and consortia have identified such regulatory elements using functional assays and evolutionary analyses; we discuss the results, strengths, and shortcomings of their approaches. We also discuss new techniques the field can leverage and emerging challenges it will face while striving to build gene regulatory maps of ever-increasing resolution and comprehensiveness.

Building integrative functional maps of gene regulation.

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hemotologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

https://www.biorxiv.org/content/biorxiv/early/2023/01/26/2023.01.25.525428.full.pdf

Structural variation across 138,134 samples in the TOPMed consortium

Unified views on variant impact across many diseases.

Evaluating the impact of genetic variants on transcriptional regulation is a central goal in biological science that has been constrained by reliance on a single reference genome. To address this, we constructed phased, diploid genomes for four cadaveric donors (using long-read sequencing) and systematically charted noncoding regulatory elements and transcriptional activity across more than 25 tissues from these donors. Integrative analysis revealed over a million variants with allele-specific activity, coordinated, locus-scale allelic imbalances, and structural variants impacting proximal chromatin structure. We relate the personal genome analysis to the ENCODE encyclopedia, annotating allele- and tissue-specific elements that are strongly enriched for variants impacting expression and disease phenotypes. These experimental and statistical approaches, and the corresponding EN-TEx resource, provide a framework for personalized functional genomics.

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Gabriel Martins

Papers

Multi-tissue integrative analysis of personal epigenomes