The Genetics of Specific Language Impairment

Specific language impairment (SLI) is diagnosed when a child has major problems in learning to talk and/or understand language, despite showing normal development in all other areas (Bishop, 2006). In this chapter we will discuss recent research on the genetics of SLI. We will introduce methods used in human genetics and describe studies in which these methods were applied. We will discuss how emerging genetic technologies may be used to investigate the molecular basis of neurodevelopmental disorders and elucidate the biological mechanisms influencing linguistic traits. Basic concepts in genetics We each carry two sets of 23 chromosomes, one set from each of our parents. These consist of two copies of chromosomes 1-22 and two sex chromosomes (females carry two X chromosomes; males have one X chromosome and one Y chromosome). A gene is a physical stretch of DNA sequence that holds the instructions for the synthesis of a functional molecule, usually a protein. Each gene may have several variants in a population, called alleles. As we have two copies of each chromosome (chromosomes 1-22), for any given variant, we can carry two identical alleles (in which case we would be homozygous for said allele), or two different alleles (in which case we would be heterozygous). The Genetics of SLI Nudel, Ceroni, Simpson & Newbury 2 Different alleles in a given gene do not necessarily have functional differences: the proteins they encode can be identical, or so similar as to have only subtle, functional differences. However, sometimes, an allele can lead to a dysfunctional protein, to various extents, and this may result in a disease or a disorder. A disorder is called recessive when it only affects people who carry two deleterious alleles in the relevant gene (or one, when the individual does not carry another allele), or dominant, if one deleterious allele is enough to cause it. In contrast, many common disorders, including SLI, are complex disorders. A complex disorder involves chance combinations of functional, but subtly different, alleles which combine across relevant biological pathways and interact with environmental factors. Different combinations confer different risks of developing the disorder. The inheritance pattern of complex disorders cannot be classified as dominant or recessive. During the creation of the sex cells, homologous chromosomes (i.e., a pair of chromosomes of the same type) cross-over and exchange DNA between them (a process called recombination), so that when one of them is passed onto the child, it is not identical to either of the copies the parent has. Instead, the chromosomes that are passed on consist of mosaics of randomly defined “parental blocks”. The probability of two ancestral alleles that are on the same chromosome being inherited together depends upon the physical distance between them. The closer the genes (or, indeed any DNA features) are, the less likely they are to be separated by a cross-over. Traditional linkage-based methods of identifying disease-causing genes (discussed below) use information on recombination events which occurred in the pedigree in order to assess linkage. Investigating the Heritability of SLI The Genetics of SLI Nudel, Ceroni, Simpson & Newbury 3 Before genetic studies of SLI can be performed, one must first evaluate its heritability using familial aggregation and twin studies. Familial aggregation studies compare the incidence of a disorder in families containing an affected proband (the individual through whom the family was identified) with that in control families. However, familial aggregation studies alone cannot exclude environmental factors. This detail requires twin studies. In a twin study, the incidence of disorder in identical co-twins of probands (monozygotic (MZ) twin concordance) is compared with that in nonidentical co-twins of probands (dizygotic (DZ) twin concordance). MZ twins are assumed to be 100% genetically similar, while DZ twins are assumed to be 50% similar. Thus, under the assumption that both twin types have a shared environment, if the MZ concordance is significantly higher than the DZ concordance, we can conclude that the disorder has a genetic component. Stromswold (1998 and 2001) reviewed several familial aggregation and twin studies of SLI and concluded that language disorders have a strong genetic component. Methods in human genetics If a disorder has a genetic component, the next step is to look for the contributory genes. We will discuss two traditional approaches to gene identification: linkage and association, and follow up with information on newer approaches. Both linkage and association methods involve the use of genetic markers, of which there are various kinds (e.g. microsatellites and Single-Nucleotide Polymorphisms (SNPs)). Markers provide points of reference in the DNA sequence allowing the tracking of parental blocks between individuals, and the identification of the genetic signature of an individual. The Genetics of SLI Nudel, Ceroni, Simpson & Newbury 4 Linkage analyses aim to identify chromosome regions that co-segregate with a disorder within family units. Linkage methods can be divided into parametric and non-parametric approaches. Parametric analyses are more powerful, but require the specification of a genetic model of the disease. This includes the inheritance pattern (e.g. whether the disease is recessive or dominant), the expected allele frequencies in the population, and the penetrance, that is, the probability of expressing a trait (the phenotype) given the set of alleles a person has (the genotype) at a given position on the chromosome (locus). When these parameters are unknown, which is often the case with complex disorders, non-parametric linkage analyses provide an alternative. Results of linkage analyses are reported as Logarithm Of Odds (LOD) scores. The LOD was originally formulated as a function of the recombination frequency (which is correlated with the distance between the marker and the conditional place of the disease-causing gene) and was defined as the base-10 logarithm of the ratio between the probability of obtaining the observed data (in terms of the number of recombination events detected in the pedigree) assuming linkage at a distance defined by r and the probability of obtaining the data assuming no linkage. However, there are different ways to calculate LOD scores depending on the test used. The higher the LOD score, the more likely it is that the disease-causing gene is located near the marker, at a distance correlated with r in the tested hypothesis. Thus, LOD scores can be maximized over r to produce a maximum LOD score for each marker (i.e. one could test linkage at different distances from each marker to find the distance which would give the highest LOD score). A LOD score of 3 is usually required to claim significant linkage, but a higher score may be required, depending on the number of markers tested and the type of analysis used. Lower LOD scores (~2) are sometimes The Genetics of SLI Nudel, Ceroni, Simpson & Newbury 5 reported as suggestive linkage. For a review of linkage methods, see Teare & Barrett (2005). In an association study, one looks for a direct statistical correlation between a marker allele and a disease in a population (assuming that the disease is caused by the marker itself or a variant close to it). These days, case-control association cohorts usually consist of large numbers (thousands) of unrelated cases and controls. However, some association methods have been developed for family-based studies. Results of association studies are usually P values, or –log10(P), when they are plotted, indicating whether a certain marker allele is significantly more frequent in cases than controls or vice versa. Association significance thresholds depend on the number of markers tested: as the number of markers increases, the required number of tests increases and the significance threshold becomes more stringent. Genome-wide association studies (GWAS) can involve in excess of a million markers, and therefore the accepted significance threshold is 5×10. In general, association studies require a higher density of markers than linkage studies, but they allow a better resolution of the identified chromosome segments. For a review of association studies for complex traits, see McCarthy et al. (2008). Whereas the methods described above use genetic markers to locate disease-causing genes, newer technologies allow researchers to obtain the sequence of a person’s entire genome. A whole-genome sequence can provide much more information about variants that may be influencing a certain trait or increase the risk of having a disorder. In fact, an ambitious project called the “1000 Genomes Project” aims to produce a catalog of most of the genetic variants with a frequency of at least 1% in several human populations studied (1000 Genomes Project Consortium, 2012). Such information may have many applications. It could be used, for example, to obtain The Genetics of SLI Nudel, Ceroni, Simpson & Newbury 6 frequencies of genetic variants in the general population, which can then be compared against a sample of individuals affected by some disorder. These data may also be used to find statistical correlations between different alleles at specific locations in the genome (i.e. the patterns in which they co-occur in different populations), which can increase the number of markers to be used in association studies in which only some of these genetic markers have been genotyped. That said, genome-wide sequencing may at times provide so much information that it becomes difficult to find the cause of a genetic disorder. Therefore, another approach, called exome sequencing, may be more appropriate in some studies. Exome sequencing entails sequencing only the parts of the genomes that contain genes (which make up about 1% of the genome). Apart from the fact that it is cheaper to sequence