Chromosomics: Bridging the Gap between Genomes and Chromosomes

Abstract

The recent advances in DNA sequencing technology are enabling a rapid increase in the number of genomes being sequenced. However, many fundamental questions in genome biology remain unanswered, because sequence data alone is unable to provide insight into how the genome is organised into chromosomes, the position and interaction of those chromosomes in the cell, and how chromosomes and their interactions with each other change in response to environmental stimuli or over time. The intimate relationship between DNA sequence and chromosome structure and function highlights the need to integrate genomic and cytogenetic data to more comprehensively understand the role genome architecture plays in genome plasticity. We propose adoption of the term 'chromosomics' as an approach encompassing genome sequencing, cytogenetics and cell biology, and present examples of where chromosomics has already led to novel discoveries, such as the sex-determining gene in eutherian mammals. More importantly, we look to the future and the questions that could be answered as we enter into the chromosomics revolution, such as the role of chromosome rearrangements in speciation and the role more rapidly evolving regions of the genome, like centromeres, play in genome plasticity. However, for chromosomics to reach its full potential, we need to address several challenges, particularly the training of a new generation of cytogeneticists, and the commitment to a closer union among the research areas of genomics, cytogenetics, cell biology and bioinformatics. Overcoming these challenges will lead to ground-breaking discoveries in understanding genome evolution and function.

Keywords: centromere; chromosome rearrangements; cytogenetics; evolution; genome biology; genome plasticity; sex chromosomes.

Figure 1

Repacking the DNA into a chromosome. The double-stranded DNA helix is wrapped around a nucleosome consisting of eight histone proteins to produce a chromatin fibre, which is attached to a backbone of non-histone proteins called scaffold proteins which form the chromosome scaffold.

Figure 2

The incremental advances made through combined cytogenetic and genomic information in the discovery of the Philadelphia chromosome causing chronic myelogenous leukemia [29,30,31,32,33] and the discovery of the sex-determining gene SRY [34,35,36,37,38].

Figure 3

The integrative breakage model, a multilayer framework for the study of genome evolution that takes into account the high-level structural organisation of genomes and the functional constraints that accompany genome reshuffling [64]. Genomes are compartmentalised into different levels of organisation that include: (i) chromosomal territories, (ii) ‘open’ (termed ‘A’)/’closed’ (termed ‘B’) compartments inside chromosomal territories, (iii) topologically associated domains (TADs) and (iv) looping interactions. TADs, which are delimited by insulating factors such as CTCF and cohesins, harbour looping topologies that permit long-range interactions between target genes and their distal enhancers, thus providing ‘regulatory neighbourhoods’ within homologous syntenic blocks (HSBs). In this context, the integrative breakage model proposes that genomic regions involved in evolutionary reshuffling (evolutionary breakpoint regions, EBRs) which will likely be fixed within populations are (i) those that contain open chromatin DNA configurations and epigenetic features that could promote DNA accessibility and therefore genomic instability, and (ii) that do not disturb essential genes and/or gene expression.