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The Genetics of Autism 6 Deborah K The Genetics of Autism 6 Deborah K. Sokol and Debomoy K. Lahiri This chapter is written to make the fast-paced, expand- an affected sibling–pair design in multiplex (having more ing field of the genetics of autism accessible to those than one affected member) families. This led to the identi- practitioners who help children with autism. New genetic fication of chromosomal abnormalities in such conditions as knowledge and technology have quickly developed over neurofibromatosis, tuberous sclerosis, and dyslexia (Smith, the past 30 years, particularly within the past decade, and 2007). Improving technology in the 1990s enabled the detec- have made many optimistic about our ability to explain tion of small genomic alterations of 50–100 kb and the direct autism. Among these advances include the sequencing of visualization of these alterations in uncultured cells via fluo- the human genome (Lander et al., 2001) and the identifi- rescent in situ hybridization (FISH). This technique ushered cation of common genetic variants via the HapMap project in the field of molecular genetics (Li & Andersson, 2009) (International HapMap Consortium, 2005), and the develop- and allowed the identification of chromosomal microdele- ment of cost-efficient genotyping and analysis technologies tions and duplications in areas of the chromosome where (Losh, Sullivan, Trembath, & Piven, 2008). Improvement in there is already high suspicion that abnormality would exist. technology has led to improved visualization of chromoso- FISH enables prenatal and cancer genetics screening and has mal abnormality down to the molecular level. The four most led to the identification of genetic aberrations associated with common syndromes associated with autism include frag- Angelman’s and Prader Willi syndromes. ile X syndrome, tuberous sclerosis, 15q duplications, and In the past decade, microarray cytogenetics has per- untreated phenylketonuria (PKU; Costa e Silva, 2008). FXS mitted the study of the entire genome on a single chip and 15q duplications are discussed within the context of cyto- with resolution as fine as a few hundred base pairs (Li & genetics. TSC is illustrated within the description of linkage Andersson, 2009). Such microarray technology represents a analysis. union between molecular genetics and classical cytogenetics. As recently reviewed (Li & Andersson, 2009), the first Two types of microarray technology are used clinically: com- inkling of chromosomal anomaly causing clinical pathology parative genomic hybridization (CGH) and single-nucleotide occurred in 1959 when an extra copy of chromosome 21 polymorphism (SNP) analysis. CGH directly measures copy was associated with the Down syndrome phenotype. Shortly number differences between a patient’s DNA and a nor- thereafter, chromosomal abnormality was recognized for mal reference DNA spanning known genes, chromosomal Patau’s syndrome (trisomy 13) and Edward’s syndrome (tri- regions, or across the entire genome. SNP analysis, on the somy 18). The chromosomal banding technique developed other hand, provides identification of a single point mutation in 1970 led to the identification of many structural chromo- via sequencing the gene in areas of suspected abnormality, somal abnormalities associated with clinical conditions. The previously identified via CGH or FISH. Another offshoot discovery that genes located close to each other on a chro- of microarray technology is submicroscopic chromosome mosome are often inherited together led to linkage analysis copy number variation (CNV) analysis, in which deletions in the 1970s and 1980s. Linkage techniques related chro- or duplications involving > 1-kb DNA have been detected mosomal abnormalities with known genetic anomalies using in patients with mental retardation, autism, and multiple congenital anomalies. There are several recent, detailed reviews of the genetics D.K. Sokol () of autism (Abrahams & Geschwind, 2008; Li & Andersson, Department of Neurology, Riley Hospital for Children, Indiana 2009; Losh et al., 2008; O’Roak & State, 2008) and this University School of Medicine, Indianapolis, IN 46202, USA chapter summarizes those reviews. The reader is encouraged e-mail: [email protected] to first review the overview of gene expression (Box 6.1) and J.L. Matson, P. Sturmey (eds.), International Handbook of Autism and Pervasive Developmental Disorders, 77 Autism and Child Psychopathology Series, DOI 10.1007/978-1-4419-8065-6_6, © Springer Science+Business Media, LLC 2011 78 D.K. Sokol and D.K. Lahiri essential nomenclature used in genetics (Box 6.2). In addi- tion, one must understand basic concepts pertinent to brain by DNA polymerases that “proofread” to ensure development (Box 6.3) and to the neurobiology of autism accuracy and repair when necessary. Despite these (Box 6.4) in order to understand its genetics. For exam- safeguards, errors called mutations can occur during ple, there is a compelling rationale that genetically directed the polymerization of this second strand. A muta- mechanisms that regulate the assembly of the brain during tion is any nucleotide sequence in a DNA molecule embryogenesis, when gone awry, may cause autism (Costa e that does not match its original DNA molecule from Silva, 2008). which it is copied. Radiation, such as ultraviolet rays and X-rays, viruses, and errors that occur dur- ing meiosis or during DNA replication can cause Box 6.1 Overview of DNA Replication and Gene errors in DNA molecules. These mutations can have Expression∗ an impact on the phenotype of an organism, espe- Genes. A gene is a unit of hereditary material located cially when they occur within the protein-coding in a specific place (locus) on a chromosome. Most sequence of the gene. Kinds of mutations include the genes carry the instructions for producing a spe- following: cific protein. A protein-coding human gene will have Frameshift Mutation: One or more bases are inserted a coding sequence, which contains the information or deleted. This can alter the entire amino acid for protein production. The coding sequence may sequence of a protein or introduce aberrant RNA be broken up into several sub-sequences, or exons, splicing. which are separated by noncoding DNA sequences, Deletion. Missing DNA sequences can range from or introns. The coding sequence is flanked by a single base pair to longer deletions involving a promoter and (usually) a 5 -untranslated region many genes in the chromosome. (5 -UTR) that occur immediately before the cod- Insertion. Additional nucleotides are inserted in the ing sequence and by a 3 -UTR and a terminator DNA sequence and can result in a nonfunctional that occur immediately after the coding sequence. protein. Promoters, terminators, UTRs, and introns can reg- Duplication (or gene amplification). Multiple copies of ulate the activity of a given gene. At a molecular a complete gene or genes, increasing the dosage of level, chromosomes are composed of long chains of genes located within chromosomes. deoxyribonucleic acid (DNA) upon which genes are Inversion. DNA sequence of nucleotides is reversed, linearly arranged. The DNA exists in a double helix either among a few bases within one gene or among and the helical strands are usually wrapped around longer DNA sequences containing several genes. histone proteins. In addition to DNA and histones, Point mutations. Known as substitutions, this is a chromosomes contain scaffolding proteins that pro- replacement of a single base nucleotide with another vide structural support and may also participate in nucleotide. gene regulation. DNA is a molecule composed of Missense mutations. A point mutation where a sin- a chain of four different types of nucleotides. It is gle nucleotide is changed to cause substitution of the sequence of these nucleotides that is the genetic a different amino acid. information that organisms inherit. DNA is double Nonsense mutation. A point mutation that results in stranded with nucleotides on each strand comple- a premature stop codon in the transcribed mRNA mentary to each other. Each strand acts as a template and possibly a nonfunctional protein product. for creating a new partner strand. This is the physical RNA splicing mutation. A point mutation that method for making copies of genes that are inher- inserts or deletes an intron/exon border neces- ited. Both individual DNA nucleotides and DNA- sary for splicing of heterogeneous nuclear RNA associated proteins can be chemically modified to to mRNA. produce epigenetic variation that may be in response Silent mutation. A point mutation that does not alter to environmental conditions and might or might not the amino acid coding for that codon. be inherited in any individual case. Epigenetic vari- Gene expression is the process in which genes express ation can significantly alter the expression level of a their functional effect through the production of pro- gene without changing its basic genetic code. teins which are responsible for most functions of DNA replication. During DNA replication, a DNA the cell. The DNA sequence of a gene is used to strand is produced from component nucleotides produce a specific protein through a ribose nucleic using its partner strand as a template. This is done acid (RNA) intermediate. Gene DNA is the map 6 The Genetics of Autism 79 which directs the production of the protein, normally OO) that produce four phenotypes: “A” (produced following a one-way pathway: by AA homozygous and AO heterozygous geno- types), “B” (produced by BB homozygous and BO →→→ heterozygous genotypes), “AB”
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