The Messenger sat down recently with Claudia Carvalho, PhD, an Assistant Investigator in the Carvalho Lab at the Pacific Northwest Research Institute, where her team explores the genetic causes of rare diseases and the biological mechanism of formation of genomic variants that impact disease expression. She has been a member of ASHG for 15 years and discussed why she has made ASHG her professional home and how the Society helps create an environment of collaboration for her work. Dr. Carvalho is currently a member of the ASHG Membership Engagement Committee. In addition to this article, watch a short video of Dr. Carvalho’s member experience.
ASHG: Tell us about your research and the focus of your lab.
Claudia Carvalho (CC): My lab is interested in defining the mutational spectrum of human genetic diseases. We are particularly interested in rare disorders that primarily affect children. In the U.S. alone, around 12 to 15 million children live with rare diseases, most of which are genetic. Despite these large numbers, millions of them remain undiagnosed, and the molecular causes of many genetic diseases are still unknown.
Mutations are ubiquitous to genomes, which makes each individual organism unique. We study the molecular features and origin of pathogenic DNA variants, particularly those leading to birth defects and neurodevelopmental diseases. We investigate how some types of DNA variants affect the local genomic architecture, sometimes with epigenetic consequences. Our research has revealed properties of regions susceptible to variation and uncovered error-prone DNA repair mechanisms responsible for formation of de novo variants. Importantly, identification of mutational patterns in germline and somatic cells reveal common molecular features that enable prediction of biological functions (and dysfunction) relevant to inform research hypothesis and potential therapeutic targets.
ASHG: You’ve been a member of ASHG for 15 years. What influenced your decision to choose ASHG as your professional home?
CC: ASHG facilitates community engagement through educational events and opportunities to volunteer for committee services. Being part of this global community has provided unique networking opportunities that support my career path in distinct stages. Moreover, the ASHG Annual Meeting is one of the largest and most internationally attended human genetic scientific conferences. It is an exciting meeting for young trainees interested in scientific engagement and learning opportunities.
ASHG: What has been your favorite research project of your career?
CC: Investigating ultra-rare and de novo variants causative of rare genetic diseases. The strong translational aspects of rare disease research, which have immediate implications for families and clinicians, make it a rewarding and motivating research area to work. The combination of a fast-evolving pace of available methodologies and the development of computational tools, fueled by a global scientific community eager to work together shapes a terrific environment for aspiring scientists. My lab is applying a multitude of novel sequencing technologies to uncover “hidden” types of DNA variants, which were nearly impossible to study just a couple of years ago. In addition, recently developed resources such as the T2T-CHM13 genome and de novo genomic assembly facilitate finding DNA alterations in complex regions of the genome such as acrocentric chromosomes and pericentromeric regions. It is a very exciting time to be part of the human genetic community.
ASHG: Are there any emerging areas of research or technology from your lab that you find particularly promising or transformative?
CC: A surprising finding from our work is the relatively high frequency of multiple structural variants occurring in cis in genomic disorders, the latter often referred to as complex genomic rearrangements (CGRs). Structural variants (SVs) are changes in the DNA that lead to amplification or deletion of a given genomic segment, change in orientation (inversions) or chance chromosomal positions through DNA insertions and translocations. SVs are believed to occur in isolation, de novo events being a known risk for genetic diseases. However, our team has shown that different types of SVs can be formed together in the same genetic event, for instance, amplifications can be generated together with a large inversion, each one of those SV may involve kilobase or megabase segments. Importantly, because CGRs can introduce a lot of DNA variation to the genome structure in just one molecular event, they are teaching us key lessons on how SVs are formed. It is for this reason that studying them fuels methodological and computational development as they often require long molecules, high accurate sequencing methodologies, manual curation, and de novo local assembly. It is a promising area of research that is also able to uncover important regulatory regions in the noncoding parts of the genome.
CGRs contribute to 28% to 40% of all the copy-number variants causing disease in neurodevelopmental and pediatric disorders such as MECP2 duplication syndrome (MRXSL, MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). Study of those disorders is providing mechanistic insights into recurrent patterns of CGRs in germline DNA variants, many of them also relevant in somatic variants. Recently, our study in a larger cohort of individuals with MRXSL uncovered the relevance of CGRs for clinical and gene expression variability. Other groups investigating inherited CGRs in large pedigrees of families with Parkinson disease show that CGRs affecting SNCA contribute disease progression. In all, the impact of CGRs as a relevant cause of genetic diseases is growing as we incorporate long-read sequencing technology to screen for pathogenic DNA variants in unsolved diagnostic families.
In cancer, CGRs are often observed as chromothripsis, a type of complex SV with tens to hundreds of breakpoint junctions, sometimes associated with characteristic high levels of genomic instability that help tumors to evade treatment. Pathogenic CGRs in rare diseases are usually less complex, stably passed on through cell divisions, and often formed de novo. Those features make studies in rare diseases an attractive model to investigate the origin and molecular features of CGRs including chromothripsis.
“Being part of this global community has provided unique networking and interaction opportunities supporting my career path in distinct stages.”
– Claudia Carvalho, PhD
ASHG: Do you collaborate with other researchers or labs through connections you’ve made through ASHG?
CC: Yes! Rare genetic diseases research requires teaming up with clinicians, researchers, families, and rare disease advocates. Our lab has built a very collaborative environment and many of the ongoing collaborations started at events supported by ASHG. The ASHG Annual Meeting is one of the main events for our lab for which we prepare our latest research to be presented and discussed with our national and international partners.
If you’re not currently an ASHG member, become a part of the ASHG community and join or renew today to take advantage of the many member benefits offered and keep updated on the latest advances in human genetics and genomics research. Contact membership@ashg.org if you have any questions!