Sequence-structure-function: uncovering how genetic variation at human centromere drives cellular phenotypes

Introduction

The last decades have seen an extraordinary leap in our knowledge of the human genome and its role in health and disease. Yet, approximately 5% of our DNA still lacks sequence annotation and has been largely excluded from functional and disease-association studies.

Genomic Gaps

These genomic gaps include DNA repeats such as centromeres, which are large tandem arrays of alpha-satellite DNA. Centromere’s chromatin is functionally essential for chromosome segregation, serving as the basal template for the mitotic kinetochore.

Recent Breakthroughs

A recent breakthrough has been the complete genome assembly, including centromeres, of a haploid cell line derived from fetoplacental growth of a molar pregnancy. However, centromeres' sequence and size vary across tissues, between individuals, and in disease states.

Research Challenges

The main challenges are to understand how centromere variation is generated and especially the consequences at a functional level.

Project Objectives

The specific objectives of my project are:

1. Identify the mutagenic processes and DNA repair responses operating at centromeres.
2. Determine the impact of centromeres’ sequence variation on chromatin structure, kinetochore function, and chromosome behavior.
3. Understand how these changes contribute to genome instability, cellular phenotypes, and disease predisposition.

Methodology

The originality of this project is to follow a multidisciplinary approach that combines experimental studies – spanning structural biochemistry to cell biology – and bioinformatic analyses. This approach will benefit from the information on centromere reference already available and soon to be generated.

Contribution to the Field

The proposed research therefore represents a very appropriate and timely contribution to provide an integrated view of human centromere variation and its role in determining phenotypic traits. Furthermore, it will provide important insight into the functional role of the “missing genome” in human diseases and promises to yield key information and tools for expanding this novel field.