My research program utilizes genetic approaches to gain a mechanistic understanding of neuropsychiatric disorders. My disease interests are Autism Spectrum Disorders (ASDs) and schizophrenia (SCZ) two highly heritable conditions that, as we have begun to discover, involve a number of overlapping genes (McCarthy et al., 2009; Sebat et al., 2009). The ultimate goal of this work is to uncover molecular pathways that could be targeted therapeutically.

To this end, we are developing novel approaches to gene discovery that are based on advanced technologies for the detection of rare variants, including studies of copy number variation (CNV) and deep whole genome sequencing (Michaelson et al.). We further investigate the pathophysiology of disease through closely integrated studies of these mutations in model systems and humans.

Copy number variation (CNV) in the human genome.

Early surveys of genetic variation found that two human chromosomes in the population differ at a rate of 0.1% on average. Individual base changes, called single nucleotide polymorphisms (SNPs), are by far the most numerous variants in the genome, but SNPs are only half of the story. The culmination of my postdoctoral research was a landmark study in 2004 (Sebat et al., 2004) that demonstrated that submicroscopic variations in DNA copy number (CNVs) are widespread in normal human genomes. On average, there are >1000 CNVs in the genome, accounting for ~4 million base pairs of genomic difference. Although SNPs outnumber CNVs in the genome by three orders of magnitude, their relative contribution to genomic variation (as measured in nucleotides) is similar. Thus, in addition to 0.1% of genetic difference at the nucleotide sequence level, we now recognize another 0.1% of genetic difference at the structural level.

The definition of a CNV continues to evolve as new classes of structural variation are revealed to us through the use of whole genome-sequencing technologies. Operationally, we define a CNV as a deletion or duplication of a genomic segment greater than 1 kb in size. In reality, variants follow a continuous distribution of size. The functional impact of CNVs is also diverse. A CNV may be large (>500 kb) and contain dozens of genes, it may disrupt or duplicate a single gene (1-100 kb in size) or it may impact only a single exon or regulatory sequence (1-1,000 bp in size).

The role of rare and de novo mutations in common disease

My initial discovery led to the hypothesis that CNVs may contribute to genetic risk for common disease. We have shown that rare CNVs play a significant role in Autism Spectrum Disorders (ASD) (Sebat et al., 2007) and schizophrenia (Malhotra et al., 2011; McCarthy et al., 2009; Vacic et al., 2011; Walsh et al., 2008). This work has led to a new paradigm for the genetic basis of psychiatric disease. It is now recognized that rare CNVs and other classes of rare genetic variation are collectively an important contributor to risk (Malhotra and Sebat, 2012).

Autism is heritable but not always inherited

In 2007, Michael Wigler and I proposed a de novo mutation model of autism. We hypothesized that genetic risk for ASD might be due, not to variants segregating within a family, but instead to mutations that arise spontaneously in the affected child. We carried out the first direct test of the de novo mutation model of ASD  by performing high resolution analysis of CNVs in autism families (Sebat et al., 2007). Our results demonstrated that de novo copy number mutations occur frequently (at a rate ~10%) in sporadic autism and rarely (at a rate of 1%) in typically-developing individuals. We further showed that the underlying mutations occurred at many different locations throughout the genome.

These results led us to conclude that de novo mutation plays an important role in the etiology of autism and that the number of different genetic loci involved is large, with each gene contributing to only a small fraction of cases. Since our initial publication, CNV- and sequencing-based studies of de novo mutation have become the predominant and demonstrably most successful strategy for identifying autism genes.

Expanding the CNV paradigm to schizophrenia and other psychiatric disorders

A genetic architecture consisting of rare and de novo CNVs is not a characteristic unique to autism or intellectual disability. In 2008, we carried out the first genetic study of CNV in schizophrenia (SCZ). By comparing the overall rate of rare CNVs in cases to that of controls, we demonstrated that there is a significant enrichment of rare variants in schizophrenia (Walsh et al., 2008). We also observed that SCZ-associated CNVs were enriched for genes involved in neurodevelopment. This study was complemented with a second family-based study which showed that de novo CNVs occur at high rates in SCZ (Malhotra et al., 2011). Based on these studies it is now recognize that schizophrenia has a genetic basis that, like autism, consists in part of rare mutations of large effect.

We have identified specific CNVs and genes that confer risk for SCZ, including loci at 7q36.3 and 16p11.2. We have shown that, in contrast to the common variants of small effect that are identified through Genome-Wide Association Studies (GWAS), these CNVs are rare variants that confer significant risk to the individual.

A rare-variant approach to the genetics of common disease

CNVs and other rare variants with large genetic effects are particularly tractable in experimental systems and in clinical studies. A disease-associated variant can yield a testable hypothesis on how gene function and biochemical pathways are impacted by the mutation. Thus CNVs may provide insights into the pathogenic mechanism of disease and identify novel targets for therapeutic intervention (Fig. 1).


Selected Publications


Malhotra, D., and Sebat, J. (2012). CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223-1241.

Malhotra, D., McCarthy, S., Michaelson, J.J., Vacic, V., Burdick, K.E., Yoon, S., Cichon, S., Corvin, A., Gary, S., Gershon, E.S. Sebat J. (2011). High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951-963.

McCarthy, S.E., Makarov, V., Kirov, G., Addington, A.M., McClellan, J., Yoon, S., Perkins, D.O., Dickel, D.E., Kusenda, M., Krastoshevsky, O., Sebat J. (2009). Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41, 1223-1227.

Michaelson, J.J., Shi, Y., Gujral, M., Zheng, H., Malhotra, D., Jin, X., Jian, M., Liu, G., Greer, D., Bhandari, A.,Sebat J. (2012). Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151, 1431-1442.

Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Wigler M. (2007). Strong association of de novo copy number mutations with autism. Science 316, 445-449.

Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M., Wigler M. (2004). Large-scale copy number polymorphism in the human genome.Science 305, 525-528.

Sebat, J., Levy, D.L., and McCarthy, S.E. (2009). Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 25, 528-535.

Vacic, V., McCarthy, S., Malhotra, D., Murray, F., Chou, H.H., Peoples, A., Makarov, V., Yoon, S., Bhandari, A., Corominas, R., Sebat J. (2011). Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471, 499-503.

Walsh, T., McClellan, J.M., McCarthy, S.E., Addington, A.M., Pierce, S.B., Cooper, G.M., Nord, A.S., Kusenda, M., Malhotra, D., Bhandari, A., King M-C, Sebat J. (2008). Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia. Science.