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Cell Genom
2022 May 11;25:. doi: 10.1016/j.xgen.2022.100132.
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Representing sex chromosomes in genome assemblies.
Carey SB
,
Lovell JT
,
Jenkins J
,
Leebens-Mack J
,
Schmutz J
,
Wilson MA
,
Harkess A
.
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Sex chromosomes have evolved hundreds of independent times across eukaryotes. As genome sequencing, assembly, and scaffolding techniques rapidly improve, it is now feasible to build fully phased sex chromosome assemblies. Despite technological advances enabling phased assembly of whole chromosomes, there are currently no standards for representing sex chromosomes when publicly releasing a genome. Furthermore, most computational analysis tools are unable to efficiently investigate their unique biology relative to autosomes. We discuss a diversity of sex chromosome systems and consider the challenges of representing sex chromosome pairs in genome assemblies. By addressing these issues now as technologies for full phasing of chromosomal assemblies are maturing, we can collectively ensure that future genome analysis toolkits can be broadly applied to all eukaryotes with diverse types of sex chromosome systems. Here we provide best practice guidelines for presenting a genome assembly that contains sex chromosomes. These guidelines can also be applied to other non-recombining genomic regions, such as S-loci in plants and mating-type loci in fungi and algae.
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Figure 1. Ideogram of human chromosomes
The human genome reference contains a single haplotype for autosomes (here only chromosomes 1 and 2 are shown, but the logic applies to all 22 autosomes). In contrast, both of the sex chromosomes are represented in a heterogametic assembly, which is important because, although they were once entirely homologous, they are highly diverged across most of their lengths. The male-specific region of the Y (MSY), also called the sex determination region (SDR), in humans has lost most genes and has accumulated many repeats, like in the ampliconic regions where the repeats have high sequence similarity (>99%) and can be found in palindromes or tandem arrays, and it has more heterochromatic regions when compared with the X. In contrast, the pseudoautosomal regions (PAR), which pair and freely recombine during meiosis, share 100% homology and are represented twice.
Figure 2. Remarkable variation found across sex chromosomes
(A) Different routes to suppressed recombination have been identified involving inversions or hemizygosity through deletions or translocations. Some SDRs have instead evolved in regions of existing low recombination, such as centromeres.
(B) The size of the SDR varies across species, with some <1 Mb, representing <1% of the sex chromosome, while others are >110 Mb and across the entirety of the sex chromosome.
(C) There are differences in which sex contains the sex-specific chromosome. In XX/XY systems, males are XY, while females are XX. In ZZ/ZW systems, the opposite is true, where females are the heterogametic sex inheriting ZW and males are ZZ. In species that have haploid sex determination, the inheritance of a single U chromosome correlates with females and a single V with males.
(D) There is also cytological variation between the homologous pairs of sex chromosomes. Some are homomorphic, where the X and Y are the same in size, while others are heteromorphic, where either the X or Y is larger. In others, the sex-specific chromosome like the Y has been lost, and dosage of genes on the X determines sex. In other systems, several chromosomes are inherited in a sex-specific fashion, called “multiple” sex chromosomes. Neo-sex chromosomes have also been identified, where a fusion between an autosomal pair and the sex chromosomes has occurred. Examples for each of these sex chromosome types can be found in Table 1.
Figure 3. Solutions for representing sex chromosomes in genome assemblies
(A) In the genome release, one option is to provide the primary haplotype for the autosomes and both pairs of the sex chromosomes, like the human reference (see Figure 1).
(B) Because the PARs will be represented twice, causing issues with downstream analyses, a solution is to mask the PARs on the Y chromosome (in blue).
(C) Assembling both haplotypes is the best solution, because the entire genome would be represented twice.
(D) These first three approaches are ideal because the location of the SDR and structural variants are maintained. The hypothetical dot plot between two haplotypes highlights a large inversion on Chr01 and several structural variants in the SDR.
(E and F) If assembling the whole chromosome is not possible, (E) the Y SDR could instead be represented as an alternative haplotype of the X or (F) as a separate contig. There are pros and cons for each of these representations of sex chromosomes in the genome (Table 2), but is imperative regardless of the approach for the SDR and PAR boundaries to be reported in the genome release, so comparative analyses can be undertaken.
