Human Medium - The Incomplete Series

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Further studies will be necessary to elucidate the potential role of HYDIN2 in brain size and in other aspects of chromosome 1q21 rearrangement phenotypes. HYDIN2 is a human-specific gene that emerged 3. Young duplicate genes can rapidly evolve essential functions [ 45 ]; however, unless increased gene dosage is itself beneficial, long-term maintenance of a duplicate gene typically requires mutational change leading to functional innovation or subfunctionalization [ 46 ].

Incomplete gene duplication provides one mechanism for rapid functional change because the duplicate differs in structure from its progenitor, with potentially profound functional consequences beyond a simple dosage increase. Interspersed duplications such as HYDIN have an additional mechanism promoting functional divergence, namely, duplicate copies in new genomic locations are subjected to asymmetric rates of mutation [ 47 ]. Because the HYDIN duplication excluded the promoter, naively one would expect the duplicate copy to have been silenced.

The acquisition of a novel promoter effectively created a fusion gene. At HYDIN2 , this promoter has driven an altered expression pattern, with widespread expression in fetal tissues, decreased expression in testis and lung, and increased expression in brain tissues cerebellum and cerebral cortex and ovary being the most prominent changes. Long-read sequencing of cDNA from both the fetal and adult brain reveals an extraordinary diversity of HYDIN2 isoforms, including the presence of additional 5' and 3' exons within transcripts spanning the duplication junctions.

Although we can confirm expression of at least three distinct HYDIN2 isoforms, we favor isoform A as the most likely protein-encoding transcript for several reasons: there is no evidence for a premature termination codon; deleterious coding mutations in the human population are rare; and the other isoforms carry an unusually large number of untranslated exons. The presence of abnormally long untranslated regions UTRs or exon junctions downstream of a premature termination codon usually indicates strong signatures for nonsense mediated decay of mRNA [ 48 ].

Similarly, a large number of 5' non-coding exons is thought to impede translational efficiency [ 49 , 50 ]. Its expression in lung and testis is consistent with the observation that recessive mutations in HYDIN cause primary ciliary dyskinesia, with the primary phenotypes being chronic respiratory infections and male infertility in humans [ 26 ]. Our copy number analyses reveal that the HYDIN2 duplication has largely fixed in the human population. In fact, HYDIN2 shows the lowest degree of copy number variation in the normal population when compared to other human-specific duplications [ 8 , 13 ].

It is plausible that altered expression or point mutations effectively disrupt HYDIN2 in these individuals or, alternatively, that HYDIN2 dysfunction does not contribute to their head circumference phenotypes. Distinguishing these possibilities and determining whether HYDIN2 plays an important role in neurodevelopment more broadly will require further functional studies complemented by large-scale genotyping in various neurodevelopmental disease cohorts and relevant, well-phenotyped controls.

In this study, we characterize the evolutionary history, transcriptional landscape, and potential clinical impact of the human-specific duplicate gene HYDIN2. We show that long-read sequencing can be used to understand a previously intractable large and complexly spliced gene and identify transcribed unannotated ORFs. Ultimately, we provide a clear example of how juxtaposition of transcriptionally active segmental duplications can lead to the birth of a new gene.

Nuclei were simultaneously DAPI stained. DAPI and Cy3 fluorescence signals, detected with specific filters, were recorded separately as grayscale images. Pseudocoloring and merging of images were performed using Adobe Photoshop software. An MSA of these non-human primates as well as the duplicated sequences from chromosomes 1 and 16 both from CH17 was created using ClustalW [ 57 ]. An unrooted phylogenetic tree was constructed in MEGA6 [ 58 ] using the neighbor-joining method [ 59 ] with complete-deletion option, yielding a total of , positions. Thus, the timing of the duplication event is estimated by taking the average evolutionary distance between the two HYDIN paralogs as a ratio of the total distance from chimpanzee HYDIN.

This yields a timing estimate of 3. For aggregate copy number estimates Fig. For paralog-specific copy number estimates Additional file 1 : Figure S3 GRCh38 was used, as recent correction to the HYDIN2 locus in the human genome made possible paralog-specific copy number estimates. Kallisto v. Transcripts per million values were then calculated using kallisto with default parameters for all of the GTEx RNA-seq samples dbGaP version phs Identical flanking sites were chosen for priming, so that relative expression of transcripts containing exon 46 could be measured in a single reaction.

The ancestral paralog was also targeted as a positive control. Individual colonies were picked and subjected to colony PCR, where the insert was amplified using standard M13 forward and reverse primers.

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The PCR products were purified and sequenced as before. Unique nucleotide differences were used to infer the paralog of origin. Primers used can be found in Additional file 1 : Table S7. Library preparation for PacBio sequencing of PCR amplicons was performed using standard and approved reagents and protocols. MIP phosphorylation, capture, and barcoding were performed as previously described [ 69 ]. Probe sequences can be found in Additional file 3 : Table S9. We used the MIPgen data analysis pipeline to map and filter reads in fastq format to a minimal human reference containing only the region containing the ancestral HYDIN paralog chr included in our MIP design with the remainder of the genome, including HYDIN2 , masked out.

This masking ensured reads mapped to only the ancestral paralog for proper variant annotation. The resulting variant set was annotated using the Ensembl Variant Effect Predictor VEP [ 71 ] using the canonical transcript for each gene. MIP capture, library preparation, massively parallel sequencing, and data analysis allowed quantification of reads derived from each HYDIN paralog over each MIP target for each individual. These data were input to a program that output paralog-specific copy number calls and detected duplications, deletions, and interlocus gene conversion events. MIP data for each individual was visualized by plotting paralog-specific HYDIN copy number point estimates across the spatial extent of sequence shared between paralogs.

The algorithmic details of this program have been previously described [ 36 ]. To enable detection of internal events, highest scoring paths through likelihood-based graphs allowing 0, 1, and 2 transitions between copy number states were considered, with the same biologically motivated restrictions on permitted transitions as previously detailed. Prior probabilities were set to reflect the observation that most humans have two copies of both HYDIN paralogs, with log-likelihoods of —15, —7. Probe sequences can be found in Additional file 3 : Table S Array CGH was performed as previously described [ 13 , 16 ] using a custom microarray Agilent with dense probe coverage across the chromosome 1q21 region.

We thank K. Munson and M. Malig for their experimental support with the sequencing of BAC clones and K. Penewit for the experimental support on the MIP-based sequencing assay. We would also like to thank H.


Mefford for the helpful discussions and support on analyzing the 1q21 patients. We also thank T. Brown for the critical review of the manuscript. MLD and XN contributed equally to this work. All authors read and approved the final manuscript. The human samples included in this study did not meet the U. All samples were publicly available or encoded, with no individual identifiers available to the study authors. Samples were collected at respective institutions after receiving informed consent and approval by the appropriate institutional review boards.

There are no new health risks to participants. Research Open Access. The birth of a human-specific neural gene by incomplete duplication and gene fusion. Genome Biology 18 Abstract Background Gene innovation by duplication is a fundamental evolutionary process but is difficult to study in humans due to the large size, high sequence identity, and mosaic nature of segmental duplication blocks.

Conclusions Together, these data support a model of rapid gene innovation by fusion of incomplete segmental duplications, altered tissue expression, and potential subfunctionalization or neofunctionalization of HYDIN2 early in the evolution of the Homo lineage.

Comparative sequencing of both human HYDIN paralogs as well as the putative integration or acceptor site in chimpanzee shows that the duplicated sequence is kbp long and shares The duplication includes 79 coding exons but excludes the sole promoter, as well as the canonical polyadenylation site, though shorter isoforms of HYDIN with earlier polyadenylation sites are recorded. For transcription to occur, this gene segment must have acquired a new promoter and at least one novel polyadenylation site, potentially from flanking sequences.

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We assessed HYDIN copy number variation across diverse human populations, archaic hominins, and non-human primate genomes by applying whole-genome shotgun sequence detection and singly unique nucleotide k-mer SUNK analysis to obtain aggregate copy number estimates [ 13 ]. In contemporary human populations, we observe a narrow distribution of HYDIN copy number, centered on individuals having two diploid copies of each paralog for a total of four aggregate copies Fig.

As expected from our phylogenetic analysis, all non-human primates have just two diploid copies of HYDIN. If all duplicated codons were maintained as in HYDIN , the theoretical alignment would yield 21 synonymous and 32 non-synonymous differences between the shared sequence, as well as three deletions Fig. Due to the deletion of exon 42 and the frameshift in exon 69, a premature stop codon is predicted.

Our results suggest that HYDIN2 acquired a new promoter and we hypothesize that the novel promoter is responsible for the expression differences between the paralogs. The latter analysis allowed us to compare expression among the different isoforms characterized by cDNA sequencing as well as quantify differences between paralogs. As an alternative approach, we sought to characterize and compare deleterious coding variation between HYDIN and HYDIN2 among probands and healthy controls from families with autism [ 43 , 44 ].

Number genotyped b n Freq. Recurrent microdeletions and microduplications at chromosome 1q21 have been associated with a variety of neurodevelopmental phenotypes, including microcephaly and macrocephaly. Loss or gain of HYDIN2 has been hypothesized to underlie these head circumference phenotypes in light of its expression in brain, its inclusion in the typical rearrangement interval, and the association of homozygous losses of HYDIN in mouse with hydrocephalus [ 22 , 24 , 25 ].

To explore this hypothesis, we leveraged our MIP assay Fig. Targeted array CGH on a subset of patients validated our whole-genome-shotgun-based and MIP-based results in every instance, confirming inclusion or exclusion of HYDIN2 among both 1q21 microduplications and microdeletions Fig. Expression quantification Kallisto v. Array CGH Array CGH was performed as previously described [ 13 , 16 ] using a custom microarray Agilent with dense probe coverage across the chromosome 1q21 region.

Acknowledgements We thank K. Consent for publication Not applicable. Ethics approval and consent to participate The human samples included in this study did not meet the U. References Ohno S. Evolution by gene duplication. Berlin: New York, Springer-Verlag; A burst of segmental duplications in the genome of the African great ape ancestor.

Evolution and diversity of copy number variation in the great ape lineage. Genome Res. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. Serial segmental duplications during primate evolution result in complex human genome architecture. Recent segmental duplications in the human genome.

Segmental duplications and copy-number variation in the human genome. Am J Hum Genet. Human adaptation and evolution by segmental duplication. Curr Opin Genet Dev. Primate segmental duplications: crucibles of evolution, diversity and disease. Nat Rev Genet. An integrated map of structural variation in 2, human genomes. Global diversity, population stratification, and selection of human copy-number variation.

Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. Diversity of human copy number variation and multicopy genes. Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. The evolution and population diversity of human-specific segmental duplications. Nat Eco Evo. Nat Genet. Finished sequence and assembly of the DUFrich 1q21 region using a haploid human genome.

BMC Genomics. Evolution of genetic and genomic features unique to the human lineage. Recurrent rearrangements of chromosome 1q N Engl J Med. Recurrent reciprocal 1q Clinical phenotype of the recurrent 1q Genet Med. Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene.

Hum Mol Genet. Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. A novel gene family NBPF: intricate structure generated by gene duplications during primate evolution. Mol Biol Evol. Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution. Human lineage-specific amplification, selection, and neuronal expression of DUF domains. Estimation of divergence times for major lineages of primate species. Genetic history of an archaic hominin group from Denisova Cave in Siberia.

A high-coverage genome sequence from an archaic Denisovan individual. The complete genome sequence of a Neanderthal from the Altai Mountains.

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Genome sequence of a 45,year-old modern human from western Siberia. Ancient human genomes suggest three ancestral populations for present-day Europeans. Rapid and accurate large-scale genotyping of duplicated genes and discovery of interlocus gene conversions. Nat Methods. Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.

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