Biology subjects

Li, A. H.

Publications and source records attributed to Li, A. H..

3 recordsLinked to original sources

bioRxiv2026

Mechanistic machine learning enables interpretable and generalizable prediction of prime editing outcomes

Although prime editing (PE) can effect virtually any specified local change to genomic DNA in living systems, its efficient application currently requires extensive optimization of prime editing guide RNA (pegRNA) sequences. We present OptiPrime, a machine learning model of PE efficiency based on our current understanding of the mechanism of prime editing. OptiPrime achieves state-of-the-art accuracy on PE efficiency prediction and also enables prediction of nicking guide RNA (PE3) and dual pegRNA (twinPE) outcomes. We validated that OptiPrime has learned the determinants of mammalian mismatch repair (MMR), and is therefore well suited for nominating MMR-evasive silent edits that improve PE efficiency. We demonstrate the utility of OptiPrime in a variety of prospective therapeutic contexts, including in primary human and mouse cells. Finally, we show how OptiPrime can be used to achieve highly streamlined and efficient in vivo correction of a pathogenic mutation in the brain of a mouse model of KIF1A-associated neurological disorder.

biochemistry↗

bioRxiv2020

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40x10-10) and ZYG11A rs74227999 (p = 2.50x10-08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males [≥] 92 years, Females [≥] 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

genetics↗

bioRxiv2019

Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the first tranche of large-scale exome sequence data for 49,960 study participants, revealing approximately 4 million coding variants (of which ~98.4% have frequency < 1%). The data includes 231,631 predicted loss of function variants, a >10-fold increase compared to imputed sequence for the same participants. Nearly all genes (>97%) had [≥]1 predicted loss of function carrier, and most genes (>69%) had [≥]10 loss of function carriers. We illustrate the power of characterizing loss of function variation in this large population through association analyses across 1,741 phenotypes. In addition to replicating a range of established associations, we discover novel loss of function variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical significance in this population, finding that 2% of the population has a medically actionable variant. Additionally, we leverage the phenotypic data to characterize the relationship between rare BRCA1 and BRCA2 pathogenic variants and cancer risk. Exomes from the first 49,960 participants are now made accessible to the scientific community and highlight the promise offered by genomic sequencing in large-scale population-based studies.

genomics↗