In Ellis’ graduate years, he studied X chromosome inactivation with Stanley Gartler at the University of Washington. As a post-doctoral fellow with Peter Goodfellow at the Imperial Cancer Research Fund, he determined the molecular structure of the region of the Y chromosome that contains the male sex-determining gene SRY (1-3) (NB: the citations refer to articles listed on the webpage called “Publication”). He obtained his first independent investigator position at the New York Blood Center, where he worked closely with James L. German III. At the Blood Center, he cloned and characterized the XG blood group gene (4,5). This work had implications for understanding long-range control of gene expression, because the XG region contains a cis-acting, polymorphic regulatory locus, referred to as XGR, that controls the expression levels of the two adjacent genes, MIC2 and XG (6).
Where Ellis truly made his mark was in the characterization of the molecular basis of the rare, autosomal recessive clinical entity Bloom’s syndrome (BS), where he made clever use of BS’s unique genetics. Approximately one third of persons with BS exhibit somatic mosaicism, that is, functionally normal and mutant cells are present in one and the same person. Ellis and German showed that homologous mitotic crossing-over between the two different mutated BLM alleles corrects one mutated BLM gene to generate a normal BLM gene on one chromosome (the gene mutated in BS is referred to as BLM). They referred to this process as somatic intragenic recombination. Somatic intragenic recombination is the major molecular mechanism that produces the mosaicism in BS but back mutation also explains some of the somatic mosaicism in BS (7,8). At least one other mechanism has been implicated through the genetic analysis. Somatic mosaicism has been described in many different autosomal recessive disorders, and understanding the molecular and cellular processes that cause it is important because rare mutation events are fundamental to the process of carcinogenesis.
Besides the inherent novelty of somatic intragenic recombination, it provided an elegant method for cloning BLM. Having identified, through the study of the somatic mosaicism in BS, recombination events within the BLM gene, the cloning of BLM followed quickly (9). BS-causing mutations in BLM were soon identified and subsequently Ellis and German showed that they could correct the cellular defect in BS by re-introducing BLM into BS cells (10,11). This work identified BLM as a critical factor in the maintenance of genome integrity, and it opened a new of field of study in humans. BLM is a member of the RecQ helicase family, a family of DNA helicases that is conserved from bacteria to mammals. Other human RecQ genes are mutated in other rare syndromes, including WRN, which is mutated in Werner syndrome, and RECQL4, which is mutated in a subset of persons with Rothmund-Thomson syndrome.
Ellis and German conducted a detailed mutational analysis of BLM in all available BS patients, identifying cryptic relatedness as a strong genetic force in human populations: persons who do not know themselves to be related can carry the same DNA change identical by descent from a recent common ancestor. This mutational analysis in BS has been a window into the importance of cryptic relatedness in different human populations (12,13).
In 1997, Ellis moved to Memorial Sloan-Kettering Cancer Center, where he was able to expand his research program to study genetic susceptibility to colorectal cancer and breast cancer. The BLM mutation blmAsh is a unique BS-causing mutation specific to Ashkenazi Jews; consequently, a straightforward PCR assay could be used to test whether BLM+/- heterozygotes are at increased risk of cancer. This was an important question because disease-gene heterozygotes are much more frequent than disease-gene homozygotes, and increased risk in heterozygotes might help explain some of the cancer susceptibility in the general population. By comparing Ashkenazi Jewish cases and controls, Ellis and collaborators found that BLM+/- heterozygotes have greater than two times the risk of developing colorectal cancer compared to BLM+/+ (14). In recent years, investigators have been returning to the idea that genetically-determined cancer susceptibility in the general population might be caused by rare mutations that have moderate effects, just as BLM+/- does (15).
Besides blmAsh, Ellis and collaborators have studied, in multiple cancer types, multiple cancer-causing mutations that are specific to the Ashkenazi Jewish population, including MSH2 A636P, the three common BRCA1/BRCA2 mutations, and CHEK2 S428F (16-20). These disease-causing mutations are in linkage disequilibrium (LD) with surrounding genetic markers. LD is defined as the excess co-occurrence of two alleles over that which is expected at random. Ellis hypothesized that the LD surrounding Jewish founder mutations might facilitate the identification of disease genes using a genome-wide association study strategy. This association strategy should have increased power to identify novel disease genes in the Jewish population, because the number of different mutations in disease genes is small (often a single mutation as is the case for blmAsh) and the length of DNA involved in the LD is large (from 1 to 10 million base pairs). As a proof of principle, his group found that they could “re-discover” BLM, MSH2, and BRCA2 using this strategy (21-22), and the strategy subsequently formed the basis of a genome-wide association study to identify breast cancer genes in Ashkenazi Jews (23).
Understanding of the genes or genetic regions identified in recent genome-wide association studies has been hampered by the difficulty in identification of the true, functionally relevant DNA changes that cause increased risk. Solving this problem will require success in two major areas: (1) genetic analysis of the risk genes using DNA sequencing, bioinformatics, and additional association analyses to identify candidate functional genetic variation and (2) functional analyses in genetic model systems (cell culture and animal models). The Ellis laboratory is combining genetic and functional analyses to identify and characterize functionally important cancer-causing genetic variation. His recent work has focused on African American colorectal cancer, where comparative population-genetic analysis is promising to shed new light on cancer susceptibility and the biological basis of cancer health disparities.