Search for Human-Specific Proteins Based on Availability Scores of Short Constituent Sequences: Identification of a WRWSH Protein in Human Testis

Abstract

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 SCSbased methods for protein searches and suggests possible contributions of SNP variants and alternative splicing of FAM75 to human evolution.

In Silico and In Vitro Evaluation of the Molecular Mimicry of the SARS-CoV-2 Spike Protein by Common Short Constituent Sequences (cSCSs) in the Human Proteome: Toward Safer Epitope Design for Vaccine Development

“…To understand how the human immune system discriminates SARS-CoV-2 proteins (nonself) from its own proteins (self), we have been using the concept of short constituent sequences (SCSs) of amino acids in proteins [77][78][79][80][81][82][83]. The idea of information extraction from protein amino acid sequences based on SCSs is as old as Chou and Fasman (1974) [84] and Garnier et al (1978) [85].…”

“…In addition to ours, there are similar but independent approaches in the literature [86][87][88][89][90][91][92][93][94][95][96][97][98][99]. The number of amino acids in an SCS unit can vary, but we primarily use five amino acids (5-aa SCSs) [77][78][79][80][81][82][83]. The 5-aa window is technically convenient because there are only 20 5 combinations of 5-aa SCSs (also called pentats in our system but called pentapeptides or pentamers in others), which is not computationally demanding.…”

“…On the contrary, our search for 5-aa SCSs can identify not only 5-aa SCSs but also longer ones simultaneously as consecutive 5-aa SCSs. Previously, our protein studies demonstrated that SCS analyses are useful for identifying protein characteristics, including secondary structures [81,82] and functional sites [79,80], and human-specific proteins [83]. Alignment-independent SCS analyses are useful for identifying commonalities (instead of similarities) that have been overlooked by conventional alignment-dependent approaches.…”

Nonself Mutations in the Spike Protein Suggest an Increase in the Antigenicity and a Decrease in the Virulence of the Omicron Variant of SARS-CoV-2

“…Although protein analysis methods based on SCSs have been developed since 2005 [52][53][54][55][56][57][58], we introduced the self/nonself concept in SCS-based analysis for the first time in a previous study [59]. In that study, we showed that when using five amino acid stretches as SCS units, most SCSs in the SARS-CoV-2 proteome are self SCSs in reference to the human proteome [59].…”

Nonself Mutations in the Spike Protein Suggest an Increase in the Antigenicity and a Decrease in the Virulence of the Omicron Variant of SARS-CoV-2

“…As a result, viral virulence may decrease. Although protein analysis methods based on SCSs have been developed since 2005 [27][28][29][30][31][32][33], we introduced the self/nonself concept in SCS-based analysis in a previous study for the first time [34]. In that study, we showed that when using 5 amino acid stretches as SCS units, most SCSs in the SARS-CoV-2 proteome are self SCSs in reference to the human proteome [34].…”