Comparative Genomic Analysis Identifies an ADP-Ribosylation Factor–like Gene as the Cause of Bardet-Biedl Syndrome (BBS3) Annie P. Chiang, Darryl Nishimura,

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Comparative Genomic Analysis Identifies an ADP-Ribosylation Factor–like Gene as the Cause of Bardet-Biedl Syndrome (BBS3) Annie P. Chiang, Darryl Nishimura, Charles Searby, Khalil Elbedour, Rivka Carmi, Amanda L. Ferguson, Jenifer Secrist, Terry Braun, Thomas Casavant, Edwin M. Stone, Val C. Sheffield The American Journal of Human Genetics Volume 75, Issue 3, Pages 475-484 (September 2004) DOI: 10.1086/423903 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 General outline of the candidate ranking process. A list of unfiltered genes (Gc) can be prioritized through a set of positive filter species (S+) on the basis of a similarity filter threshold (Th+), which yields a subset of genes (Gc+) found in all positive filter species (S+). These can be further screened with similarity filter threshold (Th-) in a set of negative filter species (S-) to yield a more restricive subset of genes (Gc+-). Further filtering continues by intersection (Λ) with additional criteria (A) to generate (Gc+,A). An even more refined set (Gc+-,A) can be obtained by intersecting Gc+,A with Gc+-. The American Journal of Human Genetics 2004 75, 475-484DOI: (10.1086/423903) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Refinement of genetic localization of the BBS3 candidate interval. The genetic map was obtained from the Marshfield Medical Clinic Web site, and the physical map distances were obtained from the UCSC Genome Browser on the basis of the July 2003 data release. Critical recombination events are also illustrated. The patient identification terminology is the same as was published previously (Sheffield et al. 1994). The American Journal of Human Genetics 2004 75, 475-484DOI: (10.1086/423903) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 BBS3 mutation (R122X) detected in a large Bedouin kindred. A, Sequence from an affected individual from the Bedouin family and a control sample, showing the homozygous C→T change that results in premature termination at codon 122. B, An example of the TaqI restriction enzyme digest that was used to confirm the R122X mutation. The mutation results in the abolition of a TaqI site within exon 7. Following TaqI digestion of a PCR fragment containing exon 7, the wild-type allele is observed as two bands (142 bp and 170 bp), whereas the uncut mutant allele produces a 312-bp fragment. For the pedigree, the hatched symbols represent BBS carriers, as determined by genetic analysis; the filled symbol denotes an individual with BBS; and the open symbols are unaffected individuals. The patient-identification terminology is the same as was published previously (Sheffield et al. 1994), with the exception of the 0, which denotes a sample that was not previously available. C, The genomic structure of the ARL6 gene is shown, with the blue shading representing the translated region. The two ARL6 isoforms that are produced by alternative splicing are shown below. The location of the R122X mutation within the ARL6 gene is indicated in red. The American Journal of Human Genetics 2004 75, 475-484DOI: (10.1086/423903) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Multiple alignment of ARL6 (HS_NP_115522) and the corresponding best BLAST hit in 11 other model organisms. The mutation (R122X) is denoted by an arrow. Each sequence is denoted by the first letter of the genus-species name, followed by a GenBank accession number (whenever possible) or a unique identifier (e.g., “DM_NP_611421” refers to the protein represented by NP_611421 in the genome of Drosophila melanogaster). Consensus residues are shown in red; conserved residues are shown in blue. Numbers flanking sequences correspond to the position of the residue within each sequence (excluding gaps). Abbreviations are as follows: HS, Homo sapiens; MM, Mus musculus; RN, Rattus norvegicus; CI, Ciona intestinalis; DM, Drosophila melanogaster; CE, Caenorhabditis elegans; TB, Trypanosoma brucei; TC, Trypanosoma cruzi; CR, Chlamydomonas reinhardtii; AN, Aspergillus nidulans; AT, Arabidopsis thaliana; and SC, Saccharomyces cerevisiae. The American Journal of Human Genetics 2004 75, 475-484DOI: (10.1086/423903) Copyright © 2004 The American Society of Human Genetics Terms and Conditions