Proteolytic activation of human-specific Olduvai domains by the furin protease.

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.

Solution NMR backbone assignments of disordered Olduvai protein domain CON1 employing Hα-detected experiments.

Olduvai protein domains, encoded by the NBPF gene family, are responsible for the largest increase in copy number of any protein-coding region in the human genome. This has spawned various genetics studies which have linked these domains to human brain development and divergence from our primate ancestors, as well as currently relevant cognitive diseases such as schizophrenia and autism spectrum disorder (ASD). There are six separate Olduvai domains which together form the majority of the various protein products of the NBPF genes.

The Driver of Extreme Human-Specific Olduvai Repeat Expansion Remains Highly Active in the Human Genome.

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 genes in the chromosomal 1q21.1-0.

Solution NMR backbone assignment reveals interaction-free tumbling of human lineage-specific Olduvai protein domains.

Olduvai protein domains, encoded primarily by NBPF genes, have been linked to both human brain evolution and cognitive diseases such as autism and schizophrenia. There are six primary domains that comprise the Olduvai family: three conserved domains (CON1-3) and three human lineage-specific domains (HLS1-3), which typically occur as a triplet (HLS1, HLS2 and HLS3). Herein, we present the solution NMR assignment of the backbone chemical shifts of the separate HLS1, 2 and 3 domains of NBPF15.

Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution.

Sequences encoding Olduvai (DUF1220) protein domains show the largest human-specific increase in copy number of any coding region in the genome and have been linked to human brain evolution. Most human-specific copies of Olduvai (119/165) are encoded by three NBPF genes that are adjacent to three human-specific NOTCH2NL genes that have been shown to promote cortical neurogenesis. Here, employing genomic, phylogenetic, and transcriptomic evidence, we show that these NOTCH2NL/NBPF gene pairs evolved jointly, as two-gene units, very recently in human evolution, and are likely co-regulated.

A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism.

Objective: The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population.

Method: The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project.

Changing the name of the NBPF/DUF1220 domain to the Olduvai domain.

We are jointly proposing a new name for a protein domain of approximately 65 amino acids that has been previously termed NBPF or DUF1220. Our two labs independently reported the initial studies of this domain, which is encoded almost entirely within a single gene family. The name Neuroblastoma Breakpoint Family ( ) was applied to this gene family when the first identified member of the family was found to be interrupted in an individual with neuroblastoma.

Genomic trade-offs: are autism and schizophrenia the steep price of the human brain?

Evolution often deals in genomic trade-offs: changes in the genome that are beneficial overall persist even though they also produce disease in a subset of individuals. Here, we explore the possibility that such trade-offs have occurred as part of the evolution of the human brain. Specifically, we provide support for the possibility that the same key genes that have been major contributors to the rapid evolutionary expansion of the human brain and its exceptional cognitive capacity also, in different combinations, are significant contributors to autism and schizophrenia.

High resolution measurement of DUF1220 domain copy number from whole genome sequence data.

Background: DUF1220 protein domains found primarily in Neuroblastoma BreakPoint Family (NBPF) genes show the greatest human lineage-specific increase in copy number of any coding region in the genome. There are 302 haploid copies of DUF1220 in hg38 (~160 of which are human-specific) and the majority of these can be divided into 6 different subtypes (referred to as clades). Copy number changes of specific DUF1220 clades have been associated in a dose-dependent manner with brain size variation (both evolutionarily and within the human population), cognitive aptitude, autism severity, and schizophrenia severity.

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases.

The copy number of DUF1220, a protein domain implicated in human brain evolution, has been linearly associated with autism severity. Given the possibility that autism and schizophrenia are related disorders, the present study examined DUF1220 copy number variation in schizophrenia severity. There are notable similarities between autism symptoms and schizophrenia negative symptoms, and divergence between autism symptoms and schizophrenia positive symptoms.

Replicated linear association between DUF1220 copy number and severity of social impairment in autism.

Sequences encoding DUF1220 protein domains exhibit an exceptional human-specific increase in copy number and have been associated with several phenotypes related to brain size. Autism is a highly heritable and heterogeneous condition characterized behaviorally by social and communicative impairments, and increased repetitive and stereotyped behavior. Given the accelerated brain growth pattern observed in many individuals with autism, and the association between DUF1220 subtype CON1 copy number and brain size, we previously investigated associations between CON1 copy number and autism-related symptoms.

Generation of mice lacking DUF1220 protein domains: effects on fecundity and hyperactivity.

Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism.

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent.

Gibbon genome and the fast karyotype evolution of small apes.

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage.

Finding and mapping new genes faster than ever: revisited.

This article recounts some of the early days of the Human Genome Project, covering the important and sometimes controversial role that complementary DNA-based approaches played in the discovery and mapping of the majority of human genes. It also describes my involvement in this effort and my lab's development of methods for rapid sequence identification and mapping of human genes.

The case for DUF1220 domain dosage as a primary contributor to anthropoid brain expansion.

Here we present the hypothesis that increasing copy number (dosage) of sequences encoding DUF1220 protein domains is a major contributor to the evolutionary increase in brain size, neuron number, and cognitive capacity that is associated with the primate order. We further propose that this relationship is restricted to the anthropoid sub-order of primates, with DUF1220 copy number markedly increasing in monkeys, further in apes, and most extremely in humans where the greatest number of copies (~272 haploid copies) is found. We show that this increase closely parallels the increase in brain size and neuron number that has occurred among anthropoid primate species.

DUF1220 protein domains drive proliferation in human neural stem cells and are associated with increased cortical volume in anthropoid primates.

Genome sequences encoding DUF1220 protein domains show a burst in copy number among anthropoid species and especially humans, where they have undergone the greatest human lineage-specific copy number expansion of any protein coding sequence in the genome. While DUF1220 copy number shows a dosage-related association with brain size in both normal populations and in 1q21.1-associated microcephaly and macrocephaly, a function for these domains has not yet been described.

Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome.

Background: Although the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.

DUF1220 dosage is linearly associated with increasing severity of the three primary symptoms of autism.

One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity.

Exome sequencing and arrayCGH detection of gene sequence and copy number variation between ILS and ISS mouse strains.

It has been well documented that genetic factors can influence predisposition to develop alcoholism. While the underlying genomic changes may be of several types, two of the most common and disease associated are copy number variations (CNVs) and sequence alterations of protein coding regions. The goal of this study was to identify CNVs and single-nucleotide polymorphisms that occur in gene coding regions that may play a role in influencing the risk of an individual developing alcoholism.

Mode of genetic inheritance modifies the association of head circumference and autism-related symptoms: a cross-sectional study.

Background: Frequently individuals with autism spectrum disorder (ASD) have been noted with a larger head circumference (HC) than their typical developing peers. Biologic hypotheses suggest that an overly rapid brain growth leads to the core symptoms of ASD by impairing connectivity. Literature is divided however where deleterious, protective and null associations of HC with ASD symptoms in individuals with ASD have been found.

Evolution of genetic and genomic features unique to the human lineage.

Given the unprecedented tools that are now available for rapidly comparing genomes, the identification and study of genetic and genomic changes that are unique to our species have accelerated, and we are entering a golden age of human evolutionary genomics. Here we provide an overview of these efforts, highlighting important recent discoveries, examples of the different types of human-specific genomic and genetic changes identified, and salient trends, such as the localization of evolutionary adaptive changes to complex loci that are highly enriched for disease associations. Finally, we discuss the remaining challenges, such as the incomplete nature of current genome sequence assemblies and difficulties in linking human-specific genomic changes to human-specific phenotypic traits.