Hongyan Li

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

BACKGROUND: Tibetans are genetically adapted to high-altitude environments. Though many studies have been conducted, the genetic basis of the adaptation remains elusive due to the poor reproducibility for detecting selective signatures in the Tibetan genomes. RESULTS: Here, we present whole-genome sequencing (WGS) data of 1001 indigenous Tibetans, covering the major populated areas of the Qinghai-Tibetan Plateau in China. We identify 35 million variants, and more than one-third of them are novel variants. Utilizing the large-scale WGS data, we construct a comprehensive map of allele frequency and linkage disequilibrium and provide a population-specific genome reference panel, referred to as 1KTGP. Moreover, with the use of a combined approach, we redefine the signatures of Darwinian-positive selection in the Tibetan genomes, and we characterize a high-confidence list of 4320 variants and 192 genes that have undergone selection in Tibetans. In particular, we discover four new genes, TMEM132C, ATP13A3, SANBR, and KHDRBS2, with strong signals of selection, and they may account for the adaptation of cardio-pulmonary functions in Tibetans. Functional annotation and enrichment analysis indicate that the 192 genes with selective signatures are likely involved in multiple organs and physiological systems, suggesting polygenic and pleiotropic effects. CONCLUSIONS: Overall, the large-scale Tibetan WGS data and the identified adaptive variants/genes can serve as a valuable resource for future genetic and medical studies of high-altitude populations.

A major obstacle in the development of superior intersubspecific hybrids between subspecies ( indica and japonica ) of Asian cultivated rice ( Oryza sativa L.) is partial sterility of the F 1 generation. Neutral genes, Sa‐n , Sb‐n , and Sc‐n , for pollen fertility have the potential to overcome F 1 pollen sterility. The present study was planned to find double‐neutral genes for pollen fertility and to evaluate their effect on pollen fertility of intersubspecific hybrids. Five genotypes were crossed with eight isogenic lines to mine neutral genes for pollen fertility. Pollen fertility of hybrids was observed in F 1 and F 2 , and segregation ratios were recorded in F 2 to confirm the neutral genes. The results showed that DN18 and DN75 had double‐neutral genes ( Sa‐n and Sb‐n ) whereas DN22 had three neutral genes Sa‐n , Sb‐n , and Sc‐n at Sa , Sb , and Sc pollen sterility loci, respectively. Furthermore, we found a single neutral gene ( Sc‐n ) for pollen fertility at the Sc locus and neutral gene for embryo sac fertility at the S5 locus in DN13. DN18 and DN75 were crossed with numerous typical japonica and indica cultivars. Results showed that double‐neutral genes could overcome most of the intersubspecific hybrid pollen sterility. These lines could be used for the development of high yielding indica × japonica hybrids and neutral genes could be introgressed into elite cultivars of Asian cultivated rice for fertility restoration.

BACKGROUND: Hispanic children with cancer experience poorer survival than their White counterparts. Infection is a known cause of cancer-related mortality; however, little is known about the risk of infection-related death among Hispanic children with cancer. We examine the association of Hispanic ethnicity with infection-related mortality and life-threatening events among children with cancer. PROCEDURE: For a cohort of all pediatric cancer patients diagnosed from 1986 to 2012 and treated at a single tertiary care center, we obtained national death records to determine all-cause mortality and infection-related mortality, as well as intensive care unit (ICU) admissions as a surrogate for life-threatening events. Cox proportional hazard models assessed all-cause mortality and infection-related mortality using ethnicity as the main independent variable. ICU admission rates were modeled using a zero-inflated Poisson regression model. Models were adjusted for gender, diagnosis year, age, residential location, and diagnosis. RESULTS: Of 6,198 patients, 741 (12%) were Hispanic. Mean follow-up was 11 years (SD = 8.04). There were 1,205 deaths, with 193 attributable to infection. Differences in all-cause mortality between Hispanic and non-Hispanic patients did not reach significance (hazard ratio [HR] = 1.14, 95% confidence interval [CI]: 0.96-1.36). However, Hispanic patients were 68% (HR = 1.68, 95% CI: 1.16-2.43) more likely to have an infection-related cause of death. Hispanic ethnicity was statistically associated with a higher rate of ICU admissions (rate ratio = 1.32, 95% CI: 1.12-1.56). CONCLUSION: Hispanic pediatric cancer patients were more likely to have an infection-related death and higher rates of ICU admissions than non-Hispanic patients. Infection may be an overlooked contributor to poorer outcomes among Hispanic patients.