Body shape and thorax

Body shape and thorax

• 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

FOXP2

• FOXP2

• Mutated in family with language disability

• ASPM/MCPH

• Mutated in individuals with microcephaly

• HAR1F

• Gene sequence highly changed in humans

• SRGAP2 (neuronal migration?)

• Partial human-specific gene duplication

• DUF1220 protein domains

• Highly increased in copy number in humans; expressed in important brain regions

Single nucleotide substitutions

• Single nucleotide substitutions

• - change gene expression

• - change gene structure

• Genome rearrangement

• Gene/segmental duplication

• - copy number change

• - value of redundancy

DUF1220 shows greatest human specific copy number expansion of any protein coding sequence in the human genome

• DUF1220 shows greatest human specific copy number expansion of any protein coding sequence in the human genome

• Show signs of positive selection

• Human increase primarily due to domain amplification (rather than gene duplication)

* Branch points in millions of years.

• * Branch points in millions of years.

Show the largest human lineage-specific increase in copy number of any protein coding region in the genome (160 HLS; >270 total in haploid genome)

• Show the largest human lineage-specific increase in copy number of any protein coding region in the genome (160 HLS; >270 total in haploid genome)

• Show signs of positive selection especially in primates

• In brain, are expressed only in neurons

• Are highly amplified in human, reduced in great apes, further reduced in monkeys, single-or-low copy in prosimians and non-primate mammals, and absent in non-mammals

• Have increased in human primarily by domain hyper-amplification involving DUF1220 triplet

Recurrent Reciprocal 1q21.1 Deletions and Duplications Associated with Microcephaly or Macrocephaly and Developmental and Behavioral Disorders

• Recurrent Reciprocal 1q21.1 Deletions and Duplications Associated with Microcephaly or Macrocephaly and Developmental and Behavioral Disorders

• 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 the copy number (dosage) of one or more genes in this region is influencing brain size in a dose-dependent manner

• These CNVs encompass or are immediately flanked by DUF1220 sequences (Dumas & Sikela, Cold Spring Harbor Symposium Quant. Biol., 2009)