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In July 2025\u2019s publication roundup we\u2019re proud to show how HiFi sequencing is playing a major role in advancing our understanding of the human brain, and autism in particular.<\/p>\n
Several new studies used long-read data to explore regions of the genome that have been historically difficult to access, including segmental duplications, repetitive DNA, and complex structural variants. From uncovering hidden mutations in well-studied autism genes to mapping human-specific gene expansions that may have shaped brain evolution, researchers are building sharper, more complete pictures of genetic variation.<\/p>\n
By combining phased genomes, methylation profiling, and capture-based enrichment with HiFi sequencing, these teams pushed past the limitations of short reads to identify rare variants with functional relevance to development and disease.<\/p>\n
See how this month\u2019s studies are helping evolve what\u2019s possible in autism research, neurogenetics, and structural variant discovery.<\/p>\n
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Brain evolution <\/a> | Pangenome discovery<\/a> | Repetitive DNA<\/a> | Structural and repeat variation<\/a> Human-specific gene expansions contribute to brain evolution<\/a><\/p>\n In this study, researchers from UC Davis, WashU, NIH, UCL and the UK generated \u201ca comprehensive resource for\u00a0studying gene expansion drivers of human brain evolution.\u201d<\/p>\n Key highlights:<\/p>\n \u201cOnly 10% of SD98 regions\u00a0[autosomal sequences sharing >98% identity with other genomic regions]\u00a0are \u2018\u2018accessible\u2019\u2019 to short reads, resulting in <10% sensitivity\u00a0to detect variants and a depletion of GWAS hits.\u201d Using the T2T-CHM13 reference, researchers identified 213 duplicated, human-specific gene families, and 1,002 paralogs\u00a0as human-specific duplicated genes\u00a0\u2014 a 5-fold increase compared to previous studies. The study included analysis of 13 priority human-specific duplicated (pHSD) gene families\u00a0representing 30 paralogs, noting \u201cnone\u00a0of the paralogs fully reside\u00a0within short-read-accessible genomic regions\u00a0due to their high identity.\u201d This included 112 HGSVC & HPRC haplotypes and\u00a0targeted\u00a0probe-based capture PacBio sequencing of 172 individuals, which: \u201cUncovered\u00a0some of this\u00a0hidden variation\u201d, \u201cdemonstrated the efficacy of long-read data to uncover hidden signatures of natural selection\u201d, and \u201cimplicates two new genes in\u00a0possibly contributing to\u00a0hallmark features of the human brain.\u201d \u201cVariants discovered using the T2T-CHM13 genome enabled the\u00a0identification of human-duplicated genes potentially contributing to traits and diseases not previously assayed in genome-wide selection screens\u201d. For example: \u201cOur analysis identified 231 SD98 genes (110 human-duplicated paralogs) co-expressed in modules enriched for autism genes, including several within disease-associated genomic hotspots.\u201d <\/p>\n \u00a0<\/p>\n Conclusion: HiFi data were essential to this study in two key ways: (1) enabling the T2T-CHM13 assembly to identify novel human duplicated genes\u2014over 30% of which were missing from the GRCh38 reference; and (2) using capture HiFi to uncover hidden variation across SDs, revealing evolutionary selection signatures. This resource paves the way for future long-read studies of variation in human populations and disease cohorts, especially autism. According to the authors, single-cell Kinnex kits are also on their radar to better define expression and isoform profiles. <\/p>\n \u00a0<\/p>\n Pangenome discovery of missing autism variants<\/a><\/p>\n In this preprint, researchers from UW, China, UCSF, NYU, Baylor, TX Children\u2019s report findings that \u201chighlight the potential of\u00a0phased genomes to discover complex more pathogenic mutations and the power of the pangenome\u00a0to restrict the focus on an increasingly smaller number of SVs\u00a0for clinical evaluation.\u201d<\/p>\n \u00a0Key highlights:\u00a0<\/p>\n Authors used\u00a0PacBio to generate \u201cphased and near-complete genome assemblies\u00a0(average contig N50=43 Mbp, QV=56)\u00a0for 189 individuals from 51 families with unsolved cases of autism.\u201d They leveraged the\u00a0HPRC\/HGSVC\u00a0pangenome\u00a0to filter out common SVs, facilitating identification of potential pathogenic variants,\u00a0to \u201cessentially exclude 99% of the more common variants\u00a0allowing us to focus on 202 private or\u00a0de novo\u00a0SV variants per child.\u201d Through this approach, they \u201cidentified three pathogenic variants \u2026, as well as nine candidate\u00a0de novo\u00a0and biparental homozygous SVs, most of which were missed by short-read sequencing.\u201d A de novo\u00a0stop-gain mutation in\u00a0SYNGAP1: \u201cnot reported in three prior SRS analyses of this family.\u201d An 874 bp\u00a0de novo\u00a0DEL in\u00a0MECP2: \u201cpreviously missed in three rounds of clinical testing, including two gene panel sequencing tests through ARUP Laboratories and Quest Diagnostics, and one test of WES through Ambry Genetics.\u201d <\/p>\n \u00a0<\/p>\n Conclusion: \u201cAdvanced sequencing techniques such as LRS will be required to reveal the full spectrum of mutations contributing to autism.\u201d <\/p>\n \u00a0<\/p>\n \u00a0<\/p>\n Long-read sequencing of trios reveals increased germline and postzygotic mutation rates in repetitive DNA<\/a>\u00a0<\/p>\n In this preprint, researchers from UW find that \u201cLRS increases DNM\u00a0[de novo mutation]\u00a0discovery by 20-40% over previous Illumina-based studies.\u201d<\/p>\n Key highlights:<\/p>\n In this study, \u201cHiFi data\u00a0[was] derived from blood and cell lines\u00a0for a total of 157 samples from 42 families affected with simplex autism.\u201d The team \u201cidentified an average of 95.3 DNM events per child\u2014a 20-40% increase in DNM discovery\u00a0per sample when compared to earlier short-read studies of the same samples\u201d, \u201cand\u00a0more than doubles the discoverable number of PZMs\u00a0[postzygotic mutations] that emerged early in embryonic development.\u201d Authors noted \u201cAnother major advantage of LRS is the ability to phase variants\u00a0assigning them unambiguously to parental haplotypes. Without pedigree information,\u00a0short-read data can typically be used to phase up to 20% of DNM calls, but we were able to phase 97.7% and 97.0% of autosomal SNVs and indels, respectively.\u201d \u201cThe\u00a0mutation rate is significantly increased for classes of repetitive DNA, where segmental duplication (SD) mutation shows a dependence on the length and percent identity of the SD.\u201d <\/p>\n \u00a0<\/p>\n Conclusion: This study reinforces the power of HiFi long-read sequencing to uncover significantly more de novo and postzygotic mutations than short reads while also enabling accurate phasing without the need for pedigree data. With near-complete resolution of variants, even in repetitive regions like SDs, HiFi sequencing provides the clarity needed to push autism genetics research forward. <\/p>\n \u00a0<\/p>\n
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