ASHG 2024 - Day 1

Bruce Gelb

He discussed the concepts of penetrance and expressivity. They are variable parameters and depend on several environmental contexts. Penetrance calculated from familial history is generally not the same as that calculated from biobank-scale population of genotyped inviduals. He argues to bring back the concept of “norms of reaction” to explain the effects of environment on gene:trait pair penetrance and expressivity.

Marie-Julie Fave

They profiled mosaic chromosal alterations (mCAs) in more than 66k samples with diverse ancestries. Quebec French Canadians (founder population) and other populations across continenets. They found genomic hotspots across continental groups (African and European). They found association of mCA with blood traits and incident cancers. Leading to clonal hematopoiesis.

Rajiv McCoy

SMC1B regulates maternal meiotic aneuploidy (?)

Less than half of human embryos leads to live births. They collected PGT-A data from Natera. They developed a hidden Markov model for inferring crossovers and aneuploidies. Aneuploidies are common in blastocyst-stage human embryos, and aneuploidy rates vary across chromosomes. Aneuploidies of maternal meiotic origin increase with maternal age, but paternal origin aneuploidy does not depend on age. Common variation in meiosis genes drives variation in crossover rate. PRDM9 in chr5 is strongly associated with crossover.

The maternal meiotic aneuploidy is associated with a locus in chr21, a haplotype spanning the meiotic cohesin component SMC1B. Aneuploidy risk allele is associated with other reproductive traits, and also reduced expression of SMC1B. Potential regulatory mechanism driving the association.

Nahyun Kong

Congenital heart disease is a genetically heterogeneous disorder. 1.3m babies are born every year with CHD.

Uniparental disomy (UPD) does not follow Mendelian inheritance. Both chromosomes are inherited from the same parents. They developed a method to detect UPD based on Mendelian violation (see PMID: 36617634).

They found that UPD is associated with 12-fold increased risk of CHD. There was a higher prevalence of maternally transmitted UPD with advanced maternal age. UPD can link maternal age with CHD.

Why won’t the mother carrying the same chromosomes develop CHD?

Giovanni Quinones-Valdez

Analysing RNA splicing using long-read RNA sequencing

Long reads demarcates different modes of splicing regulation. Alternative splicing is tissue-specific while genetic linkage is donor-specific. They developed a method to classify splicing events as predominantly influenced by either cis- or trans-directed mechanisms. They discover splicing associated variants (SAVs). The SAVs are functionally enriched in splicing QTL studies of matching tissues. SAVs are functionally enriched in RBP binding regions.

Interestingly, SAVs also overlap with risk variants for Alzheimer’s Disease.

Duncan Palmer

He talked about the Biobank Rare Variants consortium.