Common alleles tend to be more ancient than rare alleles. These common SNPs appeared thousands of years ago and reflect intricate human evolution including various adaptations, admixtures, and migration events. Eighty-four thousand abundant region-specific alleles (ARSAs) that are common in one continent but absent in the rest of the world have been characterized by processing 3100 genomes from 230 populations. Also computed were 17,446 polymorphic sites with regional absence of common alleles (RACAs), which are widespread globally but absent in one region. A majority of these region-specific SNPs were found in Africa. America has the second greatest number of ARSAs (3348) and is even ahead of Europe (1911). Surprisingly, East Asia has the highest number of RACAs (10,524) and the lowest number of ARSAs (362). ARSAs and RACAs have distinct compositions of ancestral versus derived alleles in different geographical regions, reflecting their unique evolution. Genes associated with ARSA and RACA SNPs were identified and their functions were analyzed. The core 100 genes shared by multiple populations and associated with region-specific natural selection were examined. The largest part of them (42%) are related to the nervous system. ARSA and RACA SNPs are important for both association and human evolution studies.

The public UCNEbase database, comprising 4273 human ultra-conserved noncoding elements (UCNEs), was thoroughly investigated with the aim to find any nucleotide signals or motifs that have made these DNA sequences practically unchanged over three hundred million years of evolution. Each UCNE comprises over 200 nucleotides and has at least 95% identity between humans and chickens. A total of 31,046 SNPs were found within the UCNE database. We demonstrated that every human has over 300 mutations within 4273 UCNEs. No association of UCNEs with non-coding RNAs, nor preference of a particular meiotic recombination rate within them were found. No sequence motifs associated with UCNEs nor their flanking regions have been found. However, we demonstrated that UCNEs have strong nucleotide and dinucleotide sequence abnormalities compared to genome averages. Specifically, UCNEs are depleted for CC and GG dinucleotides, while GC dinucleotides are in excess of 28%. Importantly, GC dinucleotides have extraordinarily strong stacking free-energy inside the DNA helix and unique resistance to dissociation. Based on the adjacent nucleotide stacking abnormalities within UCNEs, we conjecture that peculiarities in dinucleotide distribution within UCNEs may create unique 3D conformation and specificity to bind proteins. We also discuss the strange dynamics of multiple SNPs inside UCNEs and reasons why these sequences are extraordinarily conserved.

Long human ultra-conserved non-coding elements (UCNEs) do not have any sequence similarity to each other or other characteristics that make them unalterable during vertebrate evolution. We hypothesized that UCNEs have unique dinucleotide (DN) composition and arrangements compared to the rest of the genome. A total of 4272 human UCNE sequences were analyzed computationally and compared with the whole genomes of human, chicken, zebrafish, and fly. Statistical analysis was performed to assess the non-randomness in DN spacing arrangements within the entire human genome and within UCNEs. Significant non-randomness in DN spacing arrangements was observed in the entire human genome. Additionally, UCNEs exhibited distinct patterns in DN arrangements compared to the rest of the genome. Approximately 83% of all DN pairs within UCNEs showed significant (>10%) non-random genomic arrangements at short distances (2–6 nucleotides) relative to each other. At the extremes, non-randomness in DN spacing distances deviated up to 40% from expected values and were frequently associated with GpC, CpG, ApT, and GpG/CpC dinucleotides. The described peculiarities in DN arrangements have persisted for hundreds of millions of years in vertebrates. These distinctive patterns may suggest that UCNEs have specific DNA conformations.

We performed an exhaustive pairwise comparison of whole-genome sequences of 3120 individuals, representing 232 populations from all continents and seven prehistoric people including archaic and modern humans. In order to reveal an intricate picture of worldwide human genetic relatedness, 65 million very rare single nucleotide polymorphic (SNP) alleles have been bioinformatically processed. The number and size of shared identical-by-descent (IBD) genomic fragments for every pair of 3127 individuals have been revealed. Over 17 million shared IBD fragments have been described. Our approach allowed detection of very short IBD fragments (<20 kb) that trace common ancestors who lived up to 200,000 years ago. We detected nine distinct geographical regions within which individuals had strong genetic relatedness, but with negligible relatedness between the populations of these regions. The regions, comprising nine unique genetic components for mankind, are the following: East and West Africa, Northern Europe, Arctica, East Asia, Oceania, South Asia, Middle East, and South America. The level of admixture in every studied population has been apportioned among these nine genetic components. Genetically, long-term neighboring populations are strikingly similar to each other in spite of any political, religious, and cultural differences. The topmost admixture has been observed at the center of Eurasia. These admixed populations (including Uyghurs, Azerbaijanis, Uzbeks, and Iranians) have roughly equal genetic contributions from the Middle East, Europe, China, and India, with additional significant traces from Africa and Arctic. The entire picture of relatedness of all the studied populations unfolds and presents itself in the form of shared number/size of IBDs.

Ultraconserved elements (UCEs) are among the most evolutionarily conserved DNA sequences in vertebrate genomes, yet the biological mechanisms underlying their extraordinary conservation remain poorly understood. Using the recently developed dedUCE database comprising 12,813 human UCEs, we performed a comprehensive genome-wide analysis of their distribution relative to protein-coding genes, transcription factor (TF) genes, and long noncoding RNA (lncRNA) genes. UCEs showed a highly non-random genomic organization, with approximately 40% occurring in clusters within 20 kb genomic intervals. Non-KRAB transcription factor genes exhibited a striking sevenfold enrichment of UCEs compared with random expectation, whereas KRAB zinc-finger genes displayed an approximately tenfold depletion. Beyond TFs, UCE-rich genes were predominantly involved in developmental regulation, chromatin remodeling, RNA processing, and embryonic neurogenesis, whereas similarly large UCE-poor genes primarily encoded membrane proteins, ion channels, and synaptic components required for mature neuronal function. UCEs also demonstrated strong positional bias, with approximately fourfold enrichment near the 3′ ends of protein-coding genes but no comparable distribution pattern in lncRNAs. Although lncRNA genes showed only modest overall UCE enrichment, a small subset contained numerous UCEs. These findings demonstrate that UCEs preferentially associate with master developmental regulators rather than downstream neuronal effector genes, providing new insights into the functional organization and evolutionary conservation of the human genome.