The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Michael Wigler, Ph.D., professor, department of genetics, Cold Spring Harbor Laboratory

Speaker bio(s)

Dr. Wigler will summarize and show evidence for what we know about the genetic causes of autism, learned from examination of two cohorts: the (~2,500) SSC simplex and the (~2,000) AGRE multiplex family collections. There is statistically significant contribution from two sources: de novo mutation and transmission. De novo mutation contributes to at least 50% of cases through highly penetrant mutations that target on the order of 500 genes. About two-thirds of the contributory mutations occur in the coding region of genes, and about a third occurs deep within the introns. Many of the target genes are known with high certainty, and they appear to be under strong purifying selection in the human population. Putting together all the evidence, Dr. Wigler's laboratory has about 200 gene targets with reasonable confidence. They come from diverse functional classes, and their damage results in the degradation of intelligence and motor skills. Heredity also plays a role in autism, as evidenced by sibling concordance rates. Dr. Wigler’s laboratory shows that causal transmitted alleles come in two varieties: one that is rare and strong, and one that is not rare and presumably weak and represents shared ancestral variants. The first come predominantly from the mother, and the second appear to come in high-risk families more often from the father. Dr. Wigler’s laboratory puts these findings into the context of a gender bias of autism susceptibility and a unified genetic theory. To demonstrate the existence of transmitted causative variants that are not rare, they have used a new statistical approach based on the availability of cohorts of discordant siblings. In principle, this method can be used for any disorder to determine whether there are shared transmitted causal variants, and more speculatively, what are their cumulative contribution, source (ancient or recent), and strength (frequency).

 

If time remains, Dr. Wigler will change subjects and discuss the applications of genomic methods to two related problems in cancer diagnosis and monitoring. The first and easier problem is detecting cancer when we have “patient-specific” cancer sequence signature. When so equipped, we can detect cancer clones in tissues and blood with extreme sensitivity: on the order of one genome per million. The method may have utility in risk assessment, monitoring patient response to therapy, and alerting the early occurrence of relapse. The second and harder problem we call cancer detection without specific signature. Its application is the early detection of cancer clones in the circulation of asymptomatic people, and could be useful for monitoring people at risk for cancer, such as the genetically prone and elderly. Detection must be accompanied with a very low rate of false positive or a very good estimate of risk, and the identification of the organ of origin. This can thus be likened to: determine if a haystack contains a needle, and if so, find and thread it. The tools needed to reach these goals include: spatial genomics, error-free quantitative multiplex PCR-sequence detection, single-cell genomics, and haplotyping. The tools are not speculative, and Dr. Wigler will discuss them and their uses in this and other contexts.

 

With Drs. Richard Axel and Saul Silverstein, Dr. Wigler discovered co-transformation, a technique still used for engineering mammalian cells. His team was the first to isolate a mammalian gene using gene transfer techniques, and among the first to identify a human oncogene by this means. Dr. Wigler’s laboratory implicated three members of the RAS family in cancer; demonstrated inheritance of DNA methylation; pioneered yeast as a model to explore more complex organisms; co-invented (with Dr. Clark Still of Columbia University) encoded combinatorial synthesis, accelerating the discovery of new drug candidates; invented (with Dr. Nikolai Lisitsyn) RDA, which led to the discovery of the PTEN tumor suppressor (with Dr. Ramon Parsons of Columbia University) and the Kaposi’s sarcoma virus (by others at Columbia University); developed representational genomic approaches that are used widely in genotyping; and applied array hybridization to genomic analysis (ROMA).

 

Dr. Wigler’s current research is focused on the genomics of cancer and sporadic genetic disorders. His laboratory has demonstrated the feasibility of single-cell sequencing for genomic analysis, which will improve the targeting of cancer treatments and lead to early and less invasive tests. Dr. Wigler’s studies in human genetics led to the discovery of widespread copy number variation (CNV). This led to the hypothesis that spontaneous (de novo) mutation underlies autism and similar disorders. His recent work has demonstrated that de novo CNVs and single-nucleotide variants contribute significantly to autism.

 

Dr. Wigler received his Ph.D. in microbiology from Columbia University in 1978. That same year, he became head of the mammalian cell genetics section at Cold Spring Harbor Laboratory, where he is now professor. He is the recipient of several honors for his work, including the G.H.A. Clowes Memorial Award for Cancer Research, the Stevens Triennial Prize from Columbia University, and the Double Helix Medal. Dr. Wigler is a member of the National Academy of Sciences and a fellow of both the American Academy of Arts and Sciences and the American Academy of Microbiology.

 

Open to

Public

Host

Mary Beth Hatten, Ph.D.

Reception

Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge

Contact

Justin Sloboda

Phone

(212) 327-7785

Sponsor

Justin Sloboda
(212) 327-7785
jsloboda@rockefeller.edu