02_13.jpg Human chromosome 4

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02_03.jpg Human chromosome 17 1:6 1:36 1:10,000

Chromosome specific duplication Known as Low Copy Repeat sequences (LCRs). Mechanism: Non-Allelic Homologous Recombination (NAHR) Eichler, TIGs 17(11) p661, 2001

Paralogous Sequence similarity due to duplication events.

09_11.jpg Human clustered gene family After the segmental duplication event, genes can retain their function, but most either get deactivated, or adapt to a new function. Highly related in sequence Transcribed from the same strand

Human Genome Project Revealed a remarkably complex pattern of both ancient and recent duplications. One surprising feature is the abundance of large blocks of genomic sequences that share a high sequence homology (>90%) These blocks, defined as segmental duplications range in size from 1kb to few of hundreds of kb. Include both exonic and intronic sequences. Eichler, TIGs 17(11) p661, 2001

Unlike tandem duplications, segmental duplications are interspersed throughout the genome. A similar genomic architecture has not been observed in invertebrates genomes. Species divergence between humans and apes or old world monkeys. The human genome has undergone numerous segmental duplications during the past 35 Myr. Duplicative transposition: duplication and transposition of a genomic block of material from one chromosomal region to another. These are the segmental duplications Human Genome Project Eichler, TIGs 17(11) p661, 2001

Pattern of segmental duplication in the human genome Based on the April 2003 version of the human genome: ~5-6% of the human genome has been duplicated in recent times. There are inter-chromosomal and intra- chromosomal duplications. ~ 390 duplication hubs Zhang et al. Mol Bio and Evol 22(1) p135

LCR sequences Localized to a single chromosomal arm Many are located at the proximal euchromatic regions of chromosomes (e.g. chromosome 22). The sequences within the blocks of CSD are complex. In most cases the blocks are composed of smaller duplicons. The organization and distribution of particular modules can very substantially among the chromosome-specific duplications. Chromosome-specific duplications (CSD)

12_12.jpg >90% of the chromosome specific duplications occur within the first 10 Mb of the long arm of chromosome 22

One duplication hub in 2p11 (750kb; million years ago)

Eichler, TIGs 17(11) p661, 2001 Mosaic structure of segmental duplication Recent emerging gene families Different combination and copy number

Trans-chromosomal duplications

17p dosage changes convey phenotypes Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are dys-myelinating peripheral neuropathies that results from an altered dosage of PMP22. CMT1A results from heterozygous duplication of a 1.4 Mb segment that includes the PMP22 gene. Whereas HNPP results from a heterozygous deletion of the same genomic interval. The two diseases have dominant inheritance with germ line mutations There are also sporadic cases. Lupski and Stankiwicz, Plos Genetics 2005 p49

Recurrent rearrangements in proximal 17p Duplicated- green Deleted -red PMP22

 Sensitivity to PMP22 dosage: rare point mutations in non-duplicated patients leading to gain of function in CMT1A patients. Lupski and Stankiwicz, Plos Genetics 2005 p49 17p dosage changes convey phenotypes  Loss of function in HNPP non-deleted patients are consistent with the hypothesis.  Animal models that O.E. PM22 re-capitulated the CMT1A phenotpye.  The vast majority of unrelated CMT1A patients, as well as sporadic cases have the same size duplication.  This common duplication has recurrent breakpoints that map to low copy repeats (LCRs) called CMT1A-REP. The duplicon is a 24 kb in length.  Similarly, HNPP patients have a common deletion with recurrent breakpoints that map to CMT1A-REP.  The mechanism was shown to be non-allelic homologous recombination (NHAR) between direct oriented LCRs as substrates.  CMT1A and HNPP are alternative products of a NAHR utilizing CMT1A- REPs as recombination substrates.

copy-number variation (CNV) A type of variation that has not been included in genetic studies until recently, because it requires different detection methods, and that has only recently gained attention for its possibly important contribution to human phenotypic diversity and disease susceptibility It is defined as gain or loss of genomic segments—from over 1 kb up to several megabases—compared to a reference genome.

Copy number variations (CNVs) CGH –significantly higher resolution revealed genetic variability which was not previously anticipated (99.9% identity).

Nature 28 May 2009 Autism genome-wide copy number variation reveals ubiquitin and neuronal genes Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry Genotyped with approximately 550,000 SNPs, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)).