Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution.
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ABSTRACT:
SUBMITTER: Fiddes IT
PROVIDER: S-EPMC6611739 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Project description:Olduvai protein domains (formerly DUF1220) show the greatest human-specific increase in copy number of any coding region in the genome and are highly correlated with human brain evolution and cognitive disease. The majority of human copies are found within four NBPF genes organized in a variable number of a tandemly arranged three-domain blocks called Olduvai triplets. Here we show that these human-specific Olduvai domains are posttranslationally processed by the furin protease, with a cleavage site occurring once at each triplet. These findings suggest that all expanded human-specific NBPF genes encode proproteins consisting of many independent Olduvai triplet proteins which are activated by furin processing. The exceptional correlation of Olduvai copy number and brain size taken together with our new furin data, indicates the ultimate target of selection was a rapid increase in dosage of autonomously functioning Olduvai triplet proteins, and that these proteins are the primary active agent underlying Olduvai's role in human brain expansion.
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Project description:Previously it was found that the neuroblastoma breakpoint family (NBPF) gene repeat units of ∼1.6 kb have an important role in human brain evolution and function. The higher order organization of these repeat units has been discovered by both methods, the higher order repeat (HOR)-searching method and the HLS searching method. Using the HOR searching method with global repeat map algorithm, here we identified the tandemly organized NBPF HORs in the human and nonhuman primate NCBI reference genomes. We identified 50 tandemly organized canonical 3mer NBPF HOR copies (Olduvai triplets), but none in nonhuman primates chimpanzee, gorilla, orangutan, and Rhesus macaque. This discontinuous jump in tandemly organized HOR copy number is in sharp contrast to the known gradual increase in the number of Olduvai domains (NBPF monomers) from nonhuman primates to human, especially from ∼138 in chimpanzee to ∼300 in human genome. Using the same global repeat map algorithm method we have also determined the 3mer tandems of canonical 3mer HOR copies in 20 randomly chosen human genomes (10 male and 10 female). In all cases, we found the same 3mer HOR copy numbers as in the case of the reference human genome, with no mutation. On the other hand, some point mutations with respect to reference genome are found for some NBPF monomers which are not tandemly organized in canonical HORs.
| S-EPMC9584774 | biostudies-literature
Project description:We have established that human genome sequences encoding a novel protein domain, DUF1220, show a dramatically elevated copy number in the human lineage (>200 copies in humans vs. 1 in mouse/rat) and may be important to human evolutionary adaptation. Copy-number variations (CNVs) in the 1q21.1 region, where most DUF1220 sequences map, have now been implicated in numerous diseases associated with cognitive dysfunction, including autism, autism spectrum disorder, mental retardation, schizophrenia, microcephaly, and macrocephaly. We report here that these disease-related 1q21.1 CNVs either encompass or are directly flanked by DUF1220 sequences and exhibit a dosage-related correlation with human brain size. Microcephaly-producing 1q21.1 CNVs are deletions, whereas macrocephaly-producing 1q21.1 CNVs are duplications. Similarly, 1q21.1 deletions and smaller brain size are linked with schizophrenia, whereas 1q21.1 duplications and larger brain size are associated with autism. Interestingly, these two diseases are thought to be phenotypic opposites. These data suggest a model which proposes that (1) DUF1220 domain copy number may be involved in influencing human brain size and (2) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human lineage has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders.
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Project description:BackgroundHumans have adapted to widespread changes during the past 2 million years in both environmental and lifestyle factors. This is evident in overall body alterations such as average height and brain size. Although we can appreciate the uniqueness of our species in many aspects, molecular variations that drive such changes are far from being fully known and explained. Comparative genomics is able to determine variations in genomic sequence that may provide functional information to better understand species-specific adaptations. A large number of human-specific genomic variations have been reported but no currently available dataset comprises all of these, a problem which contributes to hinder progress in the field.ResultsHere we critically update high confidence human-specific genomic variants that mostly associate with protein-coding regions and find 856 related genes. Events that create such human-specificity are mainly gene duplications, the emergence of novel gene regions and sequence and structural alterations. 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.ConclusionsThis comprehensive study contributes to the current knowledge by considerably updating the number of human-specific genes following a critical bibliographic survey. Human-specific genes were functionally assessed for the first time to such extent, thus providing unique information. Our results are consistent with environmental changes, such as immune challenges and alterations in diet, as well as neural sophistication, as significant contributors to recent human evolution.
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Project description:Pax proteins are a family of transcription factors with a highly conserved paired domain; many members also contain a paired-type homeodomain and/or an octapeptide. Nine mammalian Pax genes are known and classified into four subgroups: Pax-1/9, Pax-2/5/8, Pax-3/7, and Pax-4/6. Most of these genes are involved in nervous system development. In particular, Pax-6 is a key regulator that controls eye development in vertebrates and Drosophila. Although the Pax-4/6 subgroup seems to be more closely related to Pax-2/5/8 than to Pax-3/7 or Pax-1/9, its evolutionary origin is unknown. We therefore searched for a Pax-6 homolog and related genes in Cnidaria, which is the lowest phylum of animals that possess a nervous system and eyes. A sea nettle (a jellyfish) genomic library was constructed and two pax genes (Pax-A and -B) were isolated and partially sequenced. Surprisingly, unlike most known Pax genes, the paired box in these two genes contains no intron. In addition, the complete cDNA sequences of hydra Pax-A and -B were obtained. Hydra Pax-B contains both the homeodomain and the octapeptide, whereas hydra Pax-A contains neither. DNA binding assays showed that sea nettle Pax-A and -B and hydra Pax-A paired domains bound to a Pax-5/6 site and a Pax-5 site, although hydra Pax-B paired domain bound neither. An alignment of all available paired domain sequences revealed two highly conserved regions, which cover the DNA binding contact positions. Phylogenetic analysis showed that Pax-A and especially Pax-B were more closely related to Pax-2/5/8 and Pax-4/6 than to Pax-1/9 or Pax-3/7 and that the Pax genes can be classified into two supergroups: Pax-A/Pax-B/Pax-2/5/8/4/6 and Pax-1/9/3/7. From this analysis and the gene structure, we propose that modern Pax-4/6 and Pax-2/5/8 genes evolved from an ancestral gene similar to cnidarian Pax-B, having both the homeodomain and the octapeptide.
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Project description:Sequences encoding Olduvai protein domains (formerly DUF1220) show the greatest human lineage-specific increase in copy number of any coding region in the genome and have been associated, in a dosage-dependent manner, with brain size, cognitive aptitude, autism, and schizophrenia. Tandem intragenic duplications of a three-domain block, termed the Olduvai triplet, in four NBPF genes in the chromosomal 1q21.1-0.2 region, are primarily responsible for the striking human-specific copy number increase. Interestingly, most of the Olduvai triplets are adjacent to, and transcriptionally coregulated with, three human-specific NOTCH2NL genes that have been shown to promote cortical neurogenesis. Until now, the underlying genomic events that drove the Olduvai hyperamplification in humans have remained unexplained. Here, we show that the presence or absence of an alternative first exon of the Olduvai triplet perfectly discriminates between amplified (58/58) and unamplified (0/12) triplets. We provide sequence and breakpoint analyses that suggest the alternative exon was produced by an nonallelic homologous recombination-based mechanism involving the duplicative transposition of an existing Olduvai exon found in the CON3 domain, which typically occurs at the C-terminal end of NBPF genes. We also provide suggestive in vitro evidence that the alternative exon may promote instability through a putative G-quadraplex (pG4)-based mechanism. Lastly, we use single-molecule optical mapping to characterize the intragenic structural variation observed in NBPF genes in 154 unrelated individuals and 52 related individuals from 16 families and show that the presence of pG4-containing Olduvai triplets is strongly correlated with high levels of Olduvai copy number variation. These results suggest that the same driver of genomic instability that allowed the evolutionarily recent, rapid, and extreme human-specific Olduvai expansion remains highly active in the human genome.
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