Deepa Pai

Bio: Deepa Pai is an academic researcher from Cold Spring Harbor Laboratory. The author has contributed to research in topics: Copy-number variation & Climatology. The author has an hindex of 4, co-authored 5 publications receiving 3387 citations.

Strong Association of De Novo Copy Number Mutations with Autism

Abstract: We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

Statistical Models for Long-range Forecasting of Southwest Monsoon Rainfall over India Using Step Wise Regression and Neural Network

Abstract: The long-range forecasts (LRF) based on statistical methods for southwest monsoon rainfall over India (ISMR) has been issued by the India Meteorological Department (IMD) for more than 100 years. Many statistical and dynamical models including the operational models of IMD failed to predict the operational models of IMD failed to predict the deficient monsoon years 2002 and 2004 on the earlier occasions and so had happened for monsoon 2009. In this paper a brief of the recent methods being followed for LRF that is 8-parameter and 10-parameter power regression models used from 2003 to 2006 and new statistical ensemble forecasting system are explained. Then the new three stage procedure is explained. In this the most pertinent predictors are selected from the set of all the potential predictors for April, June and July models. The model equations are developed by using the linear regression and neural network techniques based upon training set of the 43 years of data from 1958 to 2000. The skill of the models is evaluated based upon the validation set of 11 years of data from 2001 to 2011, which has shown the high skill on the validation data set. It can be inferred that these models have the potential to provide a prediction of ISMR, which would significantly improve the operational forecast.

Predictive relationships between Indian Ocean sea surface temperatures and Indian summer monsoon rainfall

Abstract: Monthly sea surface temperature (SST) data of 49 years (1950-98) have been analysed to examine the relationship of SST anomalies in the Indian Ocean with Indian summer monsoon rainfall (ISMR) and to derive useful predictors for long-range forecasts of ISMR. There is significant positive relationship between ISMR and SST anomalies over the Arabian Sea during November to January and also in May. SST anomalies over southeast Indian Ocean during February to March and over North Pacific during May are also positively correlated with ISMR. The composite analysis revealed that in Non-ENSO drought years (1966, 1968, 1974 and 1979) negative SST anomalies are observed over south Indian Ocean from February which slowly spread towards equator during the subsequent months. These negative SST anomalies which persist during the monsoon season may be playing an important role in modulating ISMR especially in non-ENSO years. We have derived two indices, ARBSST (SST anomalies in Arabian Sea averaged over 15o - 25o N, 50o -70o E and November-December-January) and SIOSST (SST anomalies over south Indian Ocean averaged over 15o -30o S, 70o -110o E and February and March) as useful predictors for the long-range forecasts of ISMR. The correlation coefficient (for the period 1950-98) of ARBSST and SIOSST with ISMR is 0.45 and 0.46 respectively which is statistically significant at 99.9 % level. SIOSST index has shown consistently stable relationship with ISMR. However the ARBSST index showed significant correlation with ISMR only after 1976.

Finding the missing heritability of complex diseases

Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

Synaptic, transcriptional and chromatin genes disrupted in autism

Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

The contribution of de novo coding mutations to autism spectrum disorder

Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

Abstract: It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Abstract: Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.