Shiho Endo Search for Human-Specific Proteins Based on Availability Scores of Short Constituent Sequences: Identification of a WRWSH Protein in Human Testis November 21st 2019
Little is known about protein sequences unique in humans. Here, we performed alignment-free sequence comparisons based on the availability (frequency bias) of short constituent amino acid (aa) sequences (SCSs) in proteins to search for human-specific proteins. Focusing on 5-aa SCSs (pentats), exhaustive comparisons of availability scores among the human proteome and other nine mammalian proteomes in the nonredundant (nr) database identified a candidate protein containing WRWSH, here called FAM75, as human-specific. Examination of various human genome sequences revealed that FAM75 had genomic DNA sequences for either WRWSH or WRWSR due to a single nucleotide polymorphism (SNP). FAM75 and its related protein FAM205A were found to be produced through alternative splicing. The FAM75 transcript was found only in humans, but the FAM205A transcript was also present in other mammals. In humans, both FAM75 and FAM205A were expressed specifically in testis at the mRNA level, and they were immunohistochemically located in cells in seminiferous ducts and in acrosomes in spermatids at the protein level, suggesting their possible function in sperm development and fertilization. This study highlights a practical application of SCS-based methods for protein searches and suggests possible contributions of SNP variants and alternative splicing of FAM75 to human evolution.
The human species has unique traits among animals. It is well known that morphological and physiological traits such as erect bipedalism, speech and language, and long reproductive period are very different from those of other primate species. Only humans have high intelligence that fosters sophisticated communications and complex societies. This intelligence is related to continuous brain development after birth in humans, which is not observed in great apes, including chimpanzees. The simplest hypothesis to explain human uniqueness is that it originates from the uniqueness of constituent molecules (i.e., genes and proteins) themselves. In this “constituent hypothesis,” humans have unique genes and proteins that do not exist in chimpanzees. A contrasting hypothesis is that constituent molecules are similar between humans and chimpanzees, but they are regulated differently in these species. That is, in this “regulatory hypothesis,” a similar set of proteins may be produced but at different times (heterochrony), in different locations (heterotopy), in different amounts (heterometry), and in different usage (heterotypy).
One line of support for the regulatory hypothesis comes from genomics and developmental expression studies. Following the announcement of a human genome release, the genomes of great apes were sequenced. Comparisons of DNA sequences between humans and chimpanzees have revealed that nucleotide differences are only 1.23% in aligned sequences, and most of these differences are thought to be functionally insignificant. Further rigorous comparisons throughout these genomes have revealed that nucleotide differences are 4% and that they are mostly located in noncoding regions. The expression patterns of some genes are different between humans and chimpanzees during development. Differences in transcriptomes have revealed that species differences in expression patterns are tissue-dependent and that testes have the greatest difference. It has been speculated that the accumulation of small expression or regulatory differences leads to large phenotypic differences between humans and chimpanzees. RNA-mediated mechanisms for novel genes have been proposed together with the “out of the testis” hypothesis, in which testis is considered a tissue for experimenting with new genes. Comparisons among transcriptomes in primates have revealed that many genes for spermatogenesis in testes, which likely inhibit apoptosis when mutated, are positively selected.
Although sequence alignment methods are powerful and probably the most important in comparison studies, sequences that do not contain relatively long regions of similarity cannot be compared well. In other words, short sequences that do not extend to longer similarities are discarded as noise. Although this strategy is highly successful, it assumes that nonaligned short sequences are not important, which may not always be true. There may still be important differences undiscovered where alignments are not possible.
Our SCS-based approach identified FAM75, a WRWSH-containing protein, as a candidate human-specific protein. Its uniqueness in humans may be acquired not only by a point mutation for WRWSH but also by novel alternative splicing. Together with FAM205A, FAM75 is likely expressed in human testis, and its possible expression in acrosomes suggests its potential function in fertilization and thus in human speciation.
Mainá Bitar Genes with human-specific features are primarily involved with brain, immune and metabolic evolution 22 November 2019 2
Here we critically update high confidence human-specific genomic variants that mostly associate with protein-coding regions and find 856 related genes.Functional analysis of these human-specific genes identifies adaptations to brain, immune and metabolic systems to be highly involved. We further show that many of these genes may be functionally associated with neural activity and generating the expanded human cortex in dynamic spatial and temporal contexts.
Functional differences between humans and primates are evident in major morphological features such as the skeleton (e.g. jaws and hands), hair (humans have thinner hair) and muscle tissue, and global functions including speech and language, changes in the brain have presumably had the most significant impact on the human lineage. The size of the human brain is triple. Comparative neuroanatomy has revealed a specific expansion of both the neocortex, with increase in size and neuronal interconnectivity during hominid evolution and the right side of the human brain compared to chimpanzee. While this expansion is believed to be important to the emergence of human language and other high-order cognitive functions, its genetic basis remains largely unknown.
Gennadi V. Glinsky A Catalogue of 59,732 Human-Specific Regulatory Sequences Reveals Unique-to-Human Regulatory Patterns Associated with Virus-Interacting Proteins, Pluripotency, and Brain Development 8 Jan 2020
Analysis of 4433 genes encoding virus-interacting proteins (VIPs) revealed that 95.9% of human VIPs are components of human-specific regulatory networks that appear to operate in distinct types of human cells from preimplantation embryos to adult dorsolateral prefrontal cortex. These analyses demonstrate that modern humans captured unique genome-wide combinations of regulatory sequences, divergent subsets of which are highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique-to-human mosaic of genomic regulatory patterns inherited from ECAs was supplemented with 12,486 created de novo HSRS. Genes encoding VIPs appear to represent a principal genomic target of human-specific regulatory networks, which contribute to fitness of Homo sapiens and affect a functionally diverse spectrum of biological and cellular processes controlled by VIP-containing liquid-liquid phase-separated condensates.