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DUF1220 Domains & the Search for the Genes that Made Us Human. James M. Sikela, Ph.D. Human Medical Genetics, Neuroscience, & Comparative Genomics Programs, Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine Genomics Course February 28, 2012.

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duf1220 domains the search for the genes that made us human

DUF1220 Domains & the Search for the Genes that Made Us Human

James M. Sikela, Ph.D.

Human Medical Genetics, Neuroscience, & Comparative Genomics Programs,

Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine

Genomics Course

February 28, 2012

key points
Key Points
  • First gene-based and first genome-wide study of lineage-specific gene duplication and loss in human and primate evolution
  • Dramatic human-specific increase in copy number of DUF1220 protein domains
  • DUF1220 copy number linked to evolution of brain size
  • Selection of evolutionarily adaptive genome sequences may be driving disease, e.g. 1q21.1
slide3

2 MYA

5 MYA

8 MYA

13 MYA

20 MYA

25 MYA

40 MYA

Primate Evolution

Bonobo

B/C = ~ 2

C/H = ~ 5

HC/G = ~ 8

HCG/O = ~ 13

HCG/O/Gib = ~20

Hom/OWM = ~ 25

HomOWM/NW = ~ 40

Chimp

Human

Gorilla

Orangutan

Gibbons

Old World Monkeys (e.g. baboon, rhesus, etc.)

New World Monkeys (e.g. squirrel monkey,spider monkey)

slide4

Chimpanzee

Bonobo

Orangutan

Gorilla

slide5

More Primates!

---- something has changed!

human characteristics
Body shape and thorax

Cranial properties (brain case and face)

Small canine teeth

Skull balanced upright on vertebral column

Reduced hair cover

Enhanced sweating

Dimensions of the pelvis

Elongated thumb and shortened fingers

Relative limb length

Neocortex expansion

Enhanced language & cognition

Advanced tool making

Human Characteristics

modified from S. Carroll, Nature, 2005

reports of human specific genes
Reports of “human-specific” genes
  • FOXP2
    • Mutated in family with language disability
  • ASPM/MCPH
    • Mutated in individuals with microcephaly
  • HAR1F
    • Gene sequence highly changed in humans
  • DUF1220 protein domains
    • Highly increased in copy number in humans; expressed in important brain regions
molecular mechanisms underlying genome evolution
Molecular Mechanisms Underlying Genome Evolution
  • Single nucleotide substitutions

- change gene expression & structure

  • Genome rearrangements
  • Gene duplication

- copy number change: gene dosage

- redundancy as a facilitator of innovation

gene duplication evolutionary change

Gene Duplication & Evolutionary Change

“There is now ample evidence that gene duplication is the most important mechanism for generating new genes and new biochemical processes that have facilitated the evolution of complex organisms from primitive ones.”- W. H. Li in Molecular Evolution, 1997

“Exceptional duplicated regions underlie exceptional biology”- Evan Eichler, Genome Research11:653-656, 2001

slide10

Interhominoid cDNA Array-Based Comparative Genomic Hybridization (aCGH)

Fig 1. Measuring genomic DNA copy number alteration using cDNA microarrays (array CGH). Fluorescence ratios are depicted in a pseudocolor scale, such that red indicates increased, and green decreased, gene copy number in the test (right) compared to reference sample (left).

experimental design
Experimental Design
  • Carry out pairwise cDNA aCGH comparisons between human and other hominoid species
  • Use a >39,000 cDNA microarray representing >29,000 human genes
  • Hybridize human genomic DNA (reference sequence: cy3/green) and other hominoid genomic DNAs (test sequence: cy5/red) simultaneously to the microarray
  • Visualize aCGH signals “gene-by-gene” along each chromosome across five species: human (n=5), bonobo (n=3), chimpanzee (n=4), gorilla (n=3) and orangutan (n=3)
slide14

Human & Great Ape Genes Showing Lineage-Specific Copy Number Gain/Loss

Fortna, et al, PLoS Biol. 2004

summary of human primate arraycgh results
Summary of Human/Primate ArrayCGH Results
  • First genome-wide and first gene-based aCGH comparison of human and nonhuman primate gene copy number variation (Fortna, et al 2004)
  • 1,004 (4,159) genes identified that showed lineage-specific changes in copy number
  • Time machine of evolutionary copy number change
  • Gene candidates to underlie lineage-specific traits
  • Genes identified represent most of major lineage-specific gene duplications and losses over the last 60 million years of human and primate evolution (Dumas, et al 2007)
slide17

Human & Great Ape Genes Showing Lineage-Specific Copy Number Gain/Loss

Fortna, et al, PLoS Biol. 2004

slide18

“This (Fortna, et al, 2004) is the first time that copy number changes among apes have been assayed for the vast majority of human genes, and we can expect that the biological consequences of the 140 human-specific copy number changes identified in this study will be heavily investigated over the coming years. “

---M. Hurles, PLoSBiol. 2004

slide19

DUF1220

Repeat Unit

Popesco, et al, Science 2006

slide20

InterPro-predicted DUF1220-containing proteins (NBPF family*)

*Vandepoule, et al, Mol. Biol. & Evol, 2005

slide21

Orangutan

Macaque

Bonobo

Baboon

Gibbon

Human

Gorilla

Chimp

Copy Number of DUF1220 (Q8IX62/17-33)

Sequences in Primate Species

70

60

50

Q-PCR Predicted Copy

Number

40

30

20

10

0

summary of acgh q pcr and blat results
Summary of aCGH, Q-PCR and BLAT results:
  • DUF1220 domains are highly amplified in human, reduced in great apes, further reduced in Old & New World monkeys, single or low copy non-primate mammals and absent in non-mammals
duf1220 copy number in animal genomes
DUF1220 copy number in Animal Genomes

Euarchotanglines

Laurasiatheria

Afrotheria

Metatheria

Prototheria

A total of 40 genomes were searched, but only the 22 with 4X coverage or higher are displayed.

Other Vertebrates

duf1220 copy number statistics in hg19 build
DUF1220 Copy Number Statistics in hg19 build

This table shows the unprecedented DUF1220 copy number increase in the human lineage. The primary mechanism for this expansion was domain amplification via hyper-amplification of the HLS DUF1220 triplet.

sequences encoding duf1220 domains
Sequences encoding DUF1220 domains
  • Show a major copy number burst in primates
  • Are increasingly amplified generally as a function of a species evolutionary proximity to humans, where the greatest number of copies (270) is found
  • Show signs of positive selection
  • Are highly expressed in brain regions associated with higher cognitive function
  • In brain show neuron-specific expression preferentially in cell bodies and dendrites

Popesco, et al, Science 2006

slide27

1q21.1 Deletions* Linked to Microcephaly

1q21.1 Duplications* Linked to Macrocephaly

  • Recurrent Reciprocal 1q21.1 Deletions and Duplications Associated with Microcephaly or Macrocephaly and Developmental and Behavioral Abnormalities
  • Brunetti-Pierri, et al, Nature Genetics 2008
  • Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes
  • Mefford, et al, N. Engl. J. Med. 2008

*Implies human brain size directly related to the dosage of one or more genes in these 1q21.1 CNVs

We note that these CNVs encompass or are immediately flanked by DUF1220 sequences (Dumas & Sikela, Cold Spring Harbor Symposium Quant. Biol., 2009)

copy number of genes in the 1q21 1 q21 2 region versus brain size
Copy number of genes in the 1q21.1-q21.2 region versus brain size

46 1q21.1 genes compared along with brain size across 5 primate species

DUF1220 shows the most dramatic human-specific copy number increase.

The evolutionary increase in DUF1220 copy number parallels the increase in brain size.

duf1220 copy number versus brain size
DUF1220 Copy Number Versus Brain Size

* Neandertal DUF1220 copy number is estimate based on sequence read depth from the Neandertal genome (Green et al 2010).

-but correlation is not causation

slide32
Factors that must be reconciled with model linking 1q21.1 instability, evolutionary adaptation & recurrent disease
  • Evolutionarily rapid DUF1220 copy number increase
    • Estimate, on average, 28 more DUF1220 domains added to human genome every 1 million years since Homo/Pan split
  • Underlying mechanism must account for continued, recurrent DUF1220 increases
  • Underlying mechanism must account for excess of 1q21.1 disease-associated CNVs containing dosage-sensitive genes
slide33

Proposed Mechanism Linking DUF1220, Brain Evolution and Disease

1q21.1 duplications

Macrocephaly; Autism*

1q21.1 deletions

Microcephaly; Schizophrenia*

*Diseases proposed as “Diametric Opposites” (including brain size), Crespi, Stead & Elliot, PNAS, 2009

duf1220 model
DUF1220 Model*

DUF1220 model proposes that:

1) DUF1220 copy number is directly 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

*Dumas & Sikela, Cold Spring Harbor Symposium Quant. Biol., 2009

concluding thoughts
Concluding Thoughts
  • DUF1220 domains shows the largest HLS protein coding copy number increase in the genome
    • But no one gene made us human
    • DUF1220 genotyping challenges
  • We know more about our genome than ever
    • But there are vast areas of our genome about which we know virtually nothing
    • No mammalian genome has been completely sequenced
acknowledgements
Sikela Lab

Laura Dumas

MajestaO’Bleness

Maggie Popesco

Erik MacLaren

Andy Fortna

Jan Hopkins

Jonathon Keeney

Jack Davis

Jay Jackson

Megan Sikela

Michael Cox

Kriste Marshall

Matt Brenton

Sonya Burgers

Raquel Hink

Erin Dorning

Park McNair

Collaborators

Stanford

Jon Pollack

Young Kim

Univ. of Kansas

- Gerald Wyckoff

Univ of Utah

Lynn Jorde

Baylor College

PawelStankiewicz

SauWai Cheng

UCSOM

Epidemiology

Tasha Fingerlin

Preventive Medicine & Biometrics

Anis Karimpour-Fard

Neuroscience Program

Rock Levinson

John Caldwell

Acknowledgements
a walk through our genome
A Walk Through Our Genome

--All regions of the genome are not created equal

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