Search

The development of new biomarkers for prediction and early detection of human diseases, as well as for monitoring the response to therapy is one of the most relevant areas of modern human genetics and genomics. Until recently, it was believed that the function of human Y chromosome genes was limited to determining sex and controlling spermatogenesis. Thanks to occurance of large databases of the genome-wide association study (GWAS), there has been a transition to the use of large samples for analyzing genetic changes in both normal and pathological conditions. This has made it possible to assess the association of mosaic aneuploidy of the Y chromosome in somatic cells with a shorter lifespan in men compared to women. Based on data from the UK Biobank, an association was found between mosaic loss of the Y chromosome (mLOY) in peripheral blood leukocytes and the age of men over 70, as well as a number of oncological, cardiac, metabolic, neurodegenerative, and psychiatric diseases. As a result, mLOY in peripheral blood cells has been considered a potential marker of biological age in men and as a marker of certain age-related diseases. Currently, numerous associations have been identified between mLOY and genes based on GWAS and transcriptomes in affected tissues. However, the exact cause of mLOY and the impact and consequences of this phenomenon at the whole organism level have not been established. In particular, it is unclear whether aneuploidy of the Y chromosome in blood cells may affect the development of pathologies that manifest in other organs, such as the brain in Alzheimer's disease, or whether it is a neutral biomarker of general genomic instability. This review examines the main pathologies and genetic factors associated with mLOY, as well as the hypotheses regarding their interplay. Special attention is given to recent studies on mLOY in brain cells in Alzheimer's disease., Competing Interests: The authors declare no conflict of interest., (Copyright © AUTHORS.)

Healthy human longevity is a global goal of the world health system. Determining the causes and processes influencing human longevity is the primary fundamental goal facing the scientific community. Currently, the main efforts of the scientific community are aimed at identifying the qualitative characteristics of the genome that determine the trait. At the same time, when evaluating qualitative characteristics, there are many challenges that make it difficult to establish associations. Quantitative traits are burdened with such problems to a lesser extent, but they are largely overlooked in current genomic studies of aging and longevity. Although there is a wide repertoire of quantitative trait analyses based on genomic data, most opportunities are ignored by authors, which, along with the inaccessibility of published data, leads to the loss of this important information. This review focuses on describing quantitative traits important for understanding aging and necessary for analysis in further genomic studies, and recommends the inclusion of the described traits in the analysis. The review considers the relationship between quantitative characteristics of the mitochondrial genome and aging, longevity, and age-related neurodegenerative diseases, such as the frequency of extensive mitochondrial DNA (mtDNA) deletions, mtDNA half-life, the frequency of A>G replacements in the mtDNA heavy chain, the number of mtDNA copies; special attention is paid to the mtDNA methylation sign. A separate section of this review is devoted to the correlation of telomere length parameters with age, as well as the association of telomere length with the amount of mitochondrial DNA. In addition, we consider such a quantitative feature as the rate of accumulation of somatic mutations with aging in relation to the lifespan of living organisms. In general, it may be noted that there are quite serious reasons to suppose that various quantitative characteristics of the genome may be directly or indirectly associated with certain aspects of aging and longevity. At the same time, the available data are clearly insufficient for definitive conclusions and the determination of causal relationships., Competing Interests: The authors declare no conflict of interest., (Copyright © AUTHORS.)

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

Existing human genome assemblies have almost entirely excluded repetitive sequences within and near centromeres, limiting our understanding of their organization, evolution, and functions, which include facilitating proper chromosome segregation. Now, a complete, telomere-to-telomere human genome assembly (T2T-CHM13) has enabled us to comprehensively characterize pericentromeric and centromeric repeats, which constitute 6.2% of the genome (189.9 megabases). Detailed maps of these regions revealed multimegabase structural rearrangements, including in active centromeric repeat arrays. Analysis of centromere-associated sequences uncovered a strong relationship between the position of the centromere and the evolution of the surrounding DNA through layered repeat expansions. Furthermore, comparisons of chromosome X centromeres across a diverse panel of individuals illuminated high degrees of structural, epigenetic, and sequence variation in these complex and rapidly evolving regions.

In the latest hg38 human genome assembly, centromeric gaps has been filled in by alpha satellite (AS) reference models (RMs) which are statistical representations of homogeneous higher-order repeat (HOR) arrays that make up the bulk of the centromeric regions. We analyzed these models to compose an atlas of human AS HORs where each monomer of a HOR was represented by a number of its polymorphic sequence variants. We combined these data and HMMER sequence analysis platform to annotate AS HORs in the assembly. This led to discovery of a new type of low copy number highly divergent HORs which were not represented by RMs. These were included in the dataset. The annotation can be viewed as UCSC Genome Browser custom track (the HOR-track) and used together with our previous annotation of AS suprachromosomal families (SFs) in the same assembly, where each AS monomer can be viewed in its genomic context together with its classification into one of the 5 major SFs (the SF-track). To catalog the diversity of AS HORs in the human genome we introduced a new naming system. Each HOR received a name which showed its SF, chromosomal location and index number. Here we present the first installment of the HOR-track covering only the 17 HORs that belong to SF1 which forms live functional centromeres in chromosomes 1, 3, 5, 6, 7, 10, 12, 16 and 19 and also a large number of minor dead HOR domains, both homogeneous and divergent. Monomer-by-monomer HOR annotation used for this dataset as opposed to annotation of whole HOR repeats provides for mapping and quantification of various structural variants of AS HORs which can be used to collect data on inter-individual polymorphism of AS.

Human alpha satellite (AS) sequence domains that currently function as centromeres are typically flanked by layers of evolutionarily older AS that presumably represent the remnants of earlier primate centromeres. Studies on several human chromosomes reveal that these older AS arrays are arranged in an age gradient, with the oldest arrays farthest from the functional centromere and arrays progressively closer to the centromere being progressively younger. The organization of AS on human chromosome 21 (HC21) has not been well-characterized. We have used newly available HC21 sequence data and an HC21p YAC map to determine the size, organization, and location of the AS arrays, and compared them to AS arrays found on other chromosomes. We find that the majority of the HC21 AS sequences are present on the p-arm of the chromosome and are organized into at least five distinct isolated clusters which are distributed over a larger distance from the functional centromere than that typically seen for AS on other chromosomes. Using both phylogenetic and L1 element age estimations, we found that all of the HC21 AS clusters outside the functional centromere are of a similar relatively recent evolutionary origin. HC21 contains none of the ancient AS layers associated with early primate evolution which is present on other chromosomes, possibly due to the fact that the p-arm of HC21 and the other acrocentric chromosomes underwent substantial reorganization about 20 million years ago.

Centromeric alpha satellite (AS) is composed of highly identical higher-order DNA repetitive sequences, which make the standard assembly process impossible. Because of this the AS repeats were severely underrepresented in previous versions of the human genome assembly showing large centromeric gaps. The latest hg38 assembly (GCA_000001405.15) employed a novel method of approximate representation of these sequences using AS reference models to fill the gaps. Therefore, a lot more of assembled AS became available for genomic analysis. We used the PERCON program previously described by us to annotate various suprachromosomal families (SFs) of AS in the hg38 assembly and presented the results of our primary analysis as an easy-to-read track for the UCSC Genome Browser. The monomeric classes, characteristic of the five known SFs, were color-coded, which allowed quick visual assessment of AS composition in whole multi-megabase centromeres down to each individual AS monomer. Such comprehensive annotation of AS in the human genome assembly was performed for the first time. It showed the expected prevalence of the known major types of AS organization characteristic of the five established SFs. Also, some less common types of AS arrays were identified, such as pure R2 domains in SF5, apparent J/R and D/R mixes in SF1 and SF2, and several different SF4 higher-order repeats among reference models and in regular contigs. No new SFs or large unclassed AS domains were discovered. The dataset reveals the architecture of human centromeres and allows classification of AS sequence reads by alignment to the annotated hg38 assembly. The data were deposited here: http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgt.customText=https://dl.dropboxusercontent.com/u/22994534/AS-tracks/human-GRC-hg38-M1SFs.bed.bz2.