Genome Instability & Chromosome Biology
Section Leader
Rafael Contreras, Ph.D.
Assistant Professor

My research interests are focused on investigating the function of repetitive areas of the human genome. I have a special interest in centromere genomics. The centromere is the structural unit responsible for the correct segregation of chromosomes during cell division. Destabilization of centromere function results in chromosomal mis-segregation and instability, hallmarks of fibrosis, cancers and birth defects. I am investigating the structure and evolution of centromere sequences, the epigenetic interactions of chromatin factors that modulate centromere function on centromere sequences, and the role these elements play in chromosome segregation and genome instability in non-disjunction disorders, cancers, and fibrosis. In addition, my laboratory studies the evolution and replication of endogenous and exogenous retroviruses, including HERVs, HIV and SARS-Cov-2.

Human Centromere Genomics My research has been focused on investigating Human Endogenous Retroviruses, repetitive elements that comprise 8% of the human genome. During these studies, we discovered and characterized thousands of endogenous retroviruses of the HERV-K family, in particular the types K111 and K222, which reside in the centromeres of the human genome (Contreras-Galindo et al. 2013; Zahn et al. 2015). These findings are giving us the opportunity to study human centromere genomics, regions of the human genome that have been extremely difficult to annotate because of the repetitive nature of these areas, and therefore, remain a last frontier of human genetics. Sequence analysis of centromere retroviruses revealed that, surprisingly, human centromeres have been under continuous reshuffling during evolution and exchanged genetic material at rates higher than other areas of the chromosomes. We are also characterizing other centromere repetitive elements, the so-called alpha repeats, which are the main arrays of repetitive elements in human centromeres and that are found in a unique structure in each human chromosome. In the last years I have annotated centromere sequences to fill the gaps of human centromere maps. This is very important for human genomics, as recent evidence from our lab and other investigators has indicated that specific alpha repeats recruit centromeric chromatin factors that assemble the kinetochore. We have identified markers for multiple centromere arrays in each human chromosome and developed molecular tools to study these elements. Using these markers, we have identified startling evidence of extensive centromere DNA instability in disorders characterized by chromosome missegregation such as trisomy 21, as well as scleroderma fibrosis and cancers. We plan to study the effect of centromere instability in centromere function and chromosome instability in these diseases.

Centromeres in Scleroderma We have a special attention on the function of centromeres in Scleroderma. The contribution of centromere defects to Scleroderma remain unknown despite many of the centromere proteins were discovered due to these patient-derived antibodies. Using novel genetic and cytogenetic analysis we find that affected fibroblasts from SSc patients show marked alterations in centromeric DNA regardless of receiving treatment. Strikingly, we observed “leaking” of centromere proteins from the nucleus into the cytoplasm in all limited cutaneous Scleroderma patients who have anticentromere antibodies. Scleroderma fibroblasts showed abnormal chromosome segregation, with aneuploidy (only in diffuse cutaneous Scleroderma) and micronuclei (in all types of disease). Surprisingly, several micronuclei no longer recruit the centromere identity protein CENPA, despite they still retain centromere sequences. Our studies reveal that centromeric genomic instability and epigenetic defects may lead to the pathogenesis of Scleroderma. As both centromere genetics and epigenetics defects, together with an immune response to centromeres is seen in Scleroderma patients, we are clarifying whether Scleroderma is a centromere disease with very promising findings. The projects are currently supported by the Scleroderma Foundation and the Rheumatology Research Foundation.

Evolution of SARS-CoV-2 Our laboratory use recombination analysis and Bayesian Bioinformatics to follow the evolution of viruses. Using these type of analysis, we focus on the discovery of new strains of SARS-CoV-2 emerging during the 2019-2020 pandemic.

Primary Research Areas:

  • Chromosome Biology
  • Molecular Biology
  • Genetics and Genomics
  • Endogenous Retroviruses
  • SARS-CoV-2 Evolution

Research Specialties:

  • Pathogenesis of Fibrosis and Cancer
  • Genomics of Human Centromeres
  • DNA instability and Repair of Centromeres
  • Genome Editing of centromeres
  • Evolution of Endogenous and Exogenous Retroviruses (HERV-K, SARS-CoV-2)