Search

This protocol generates consensus tandem repeat genotypes by integrating calls from the tools HipSTR, GangSTR, adVNTR and ExpansionHunter and provides guidance for population-level identification of complex trait associations.

Melissa Gymrek and colleagues estimate mutation parameters for each short tandem repeat (STR) in the human genome. They find that local sequence features impact these estimates and they create a framework for measuring constraint at STRs by comparing observed and expected mutation rates, providing a tool for prioritizing pathogenic variants.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

A pangenome is a collection of DNA sequences that reveals genetic variation between individuals. Four scientists discuss the generation of a human pangenome, and what insights can be gained from it.

A bioinformatics pipeline to identify tandem repeat mutations is developed and used to characterize precise changes in repeat copy number associated with autism spectrum disorder.

Disparities in skin cancer diagnosis remain across different ancestries and sociodemographic groups. Here, the authors identify genetic ancestry, lifestyle, social determinants of health, and PDE5a inhibitor use as independent risk factors for skin cancer in the All of Us dataset, and integrate these factors into an XGBoost multiethnic model for identifying patients with skin cancer.

In this Comment, Lamkin and Gymrek discuss recent results that suggest that the systematic incorporation of tandem repeats into complex trait analyses will yield a rich source of causal variants and new biological insights.

Tandem repeats (TRs) comprise some of the most polymorphic regions of the human genome but are difficult to study. Here, the authors develop an ensemble-based genotyping method and characterize 1.7 million TRs across 3,550 humans from diverse populations.

Genetic analysis of paternal sperm from families with a child affected by autism reveals that the recurrent risk for transmitting disease-associated de novo mutations to future offspring is near 0% for most couples but is substantially higher for a small fraction of couples.

Single-molecule sequencing of poly(A)-tailed chromatin immunoprecipitated DNA proves equal in sensitivity and accuracy to amplification-based sequencing technologies and allows analysis of samples sizes as small as 50 pg.

A truth-set catalog of human tandem repeats allows benchmarking of variant analysis tools.

Short-tandem repeats (STR), similar to single nucleotide polymorphisms (SNP), contribute to complex traits, but their ascertainment by next-generation sequencing is costly. Here, Saini et al. provide a SNP+STR haplotype reference panel that allows imputation of STRs from SNP array data.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

The transcription process of DNA is highly complex and while short DNA sequence motifs recognized by transcription factors are well known, less is known about the context in the DNA sequence that determines whether a transcription factor will actually bind its motif. Zheng and colleagues present a method that uses convolutional neural networks to identify sequence features that help predict whether transcribing proteins can bind to their target sequences in DNA.

Variable number tandem repeats (VNTRs) are implicated in human diseases yet have been difficult to analyse computationally. Here, the authors describe a neural network method, adVNTR-NN, that allows rapid and accurate genotyping of VNTRs from large whole genome sequencing datasets.

Interactions between germline variants and somatic mutations is a relatively unexplored topic in cancer. Here, in Ewing sarcoma, the authors show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls MYBL2, whose high expression correlates with prognosis.

Deep whole-genome sequencing of 300 individuals from 142 diverse populations provides insights into key population genetic parameters, shows that all modern human ancestry outside of Africa including in Australasians is consistent with descending from a single founding population, and suggests a higher rate of accumulation of mutations in non-Africans compared to Africans since divergence.

Chris Tyler-Smith, Carlos Bustamante and colleagues report an analysis of 1,244 human Y chromosomes from the 1000 Genomes Project. They find that copy number variants have a higher predicted functional impact than other variant classes and infer bursts of male population expansion corresponding to historical periods of migration and technological innovations.

Analysis of whole-genome sequencing and expression data for 17 tissues identifies short tandem repeats whose repeat number is associated with gene expression (eSTRs). Specific eSTRs are implicated in different complex traits through colocalization analysis with known genome-wide association study signals.

HipSTR accurately genotypes and phases short tandem repeats, enabling robust genome-wide analyses of short tandem repeat variations.

Yaniv Erlich and colleagues report a genome-wide survey of the contribution of short tandem repeats (STRs) to gene expression in humans and identify 2,060 significant expression STRs (eSTRs). They find that eSTRs contribute 10–15% of the cis heritability mediated by all common variants and are associated with various clinically relevant phenotypes.