Variations existing in the human genome fall into two major sections: sequence repeats and polymorphisms. Essay

Variations existing in the human genome fall into two major sections: sequence repeats and polymorphisms. Essay

1.0 Sequence Repeats.

Sequence repeats consists of two categories, viz., (1) Minisatellites, alternatively referred to as variable number tandem repeats (VNTR) comprise of repeats ranging from 12 to 500 base pairs. An estimated 80% of humans have variable number of repeats in minisatellites. (2) Microsatellites,  are often called short tandem repeats (STR), or, simple sequence repeats (SSR) with repeats comprising approximately 1 to 11 base pairs. Microsatellites are short stretches of repeated DNA found in most genomes that are highly polymorphic. About 0.5% of the human genome is composed of microsatellites and there are a reported 80,000 dinucleotide and 60,000 trinucleotide repeats which are variable in nature (Senate Commission on Genetic Research). They are composed of short segments of DNA consisting of repeated sequences, sandwiched between flanking sequences. Microsatellites are present in the non – coding region of DNA so they do not have any apparent phenotypic effects. Some examples of microsatellites repeat sequences (The Sanger Institute):

Mononucleotide SSR (A)11: AAAAAAAAAAA
Dinucleotide SSR (GT)6: GTGTGTGTGTGT
Trinucleotide SSR (CTG)4: CTGCTGCTGCTG

The repeated sequence may exist in a large variety of numbers. Sometimes, microsatellites initiate the DNA polymerase to synthesise extra copies of the repeats, which are then passed on to the offspring (Massachusetts Institute of Technology, Department of Biology).

With reproduction, microsatellites undergo recombination, and a given population maintains a set of microsatellites that is unique for that specific population.

The figure below illustrates a simplified procedure for microsatellite detection. PCR primers are designed for a certain region in the genome and which pair on either side of the repeated sequence. A single pair PCR primer yield differently sized products for different lengths of a microsatellite sequence.

Figure 2. Microsatellite detection from gDNA using PCR technique. Two PCR primers (forward and reverse lightly shaded arrows) are designed to flank the microsatellite region. If there were no repeats, the PCR product would be 100 bp in length. Therefore, by determining the size of each PCR product (in this case 116 bp), the number of CA repeats are present in each microsatellite can be calculated (8 CA repeats in this illustration). Courtesy: Davidson College, Department of Biology

PCR products are separated by gel or capillary electrophoresis. From the results obtained, the number of repeat sequences for each allele can be determined. It is noteworthy to mention that microsatellite data often produce minor bands (stutter bands) in addition to major ones. Such stutter bands normally differ from major bands by 2 nucleotides.

Figure 3a. Four sets of data from gel electrophoresis portraying major (dark) and minor (light) bands. MW molecular weight standards. Courtesy: Davidson College

Figure 3b. Data produced by automated capillary electrophoresis based DNA sequencer. These are line graphs, and the location of each peak on the X axis represents a different sized PCR product and height of each peak determines the amount of product. Major bands produce higher peaks in comparison to minor bands. MW molecular weight standards. Courtesy: Davidson College

The variability of microsatellites has made it a popular genetic marker for use in genotyping applications such as medical genetics, forensics (Hoff-Olsen et al. 2001 and Szibor et al. 2003), genetic mapping, human population studies (Bindu et al. 2005) and diagnosis and identification of human diseases.

Microsatellites were originally employed for genetic mapping but now are widely used in oncology research (Lamberti et al. 1999 and Chialina et al. 2006). The polymorphic natures of microsatellites make them useful in linkage studies which attempt to locate genes responsible for various genetic disorders.

1.1 Polymorphisms

Figure 4. The diagram illustrates SNPs at 28 base pairs (bp) position. Courtesy: Chinese Medical and Biological Information.

Polymorphisms are primarily composed of single nucleotide polymorphisms(SNPs), which is gene variability occurring at high frequencies in the human genome (Gray et al. 2000). Multiple alternative alleles occurring on a gene locus in a population with a defined frequency is called SNPs. Frequency of the rare allele or nucleotide is a minimum 1%. These variations are important information for phenotypic differentiation in a population (Weiss et al. 2000). Unlike microsatellites, SNPs occur both in the non – coding and coding regions (cSNPs). From an approximate total of 11 million SNPs, 2.1 million have been discovered (Senate Commission on Genetic Research).

Almost a decade ago, STRs were popular markers used by molecular biologists to screen single gene disorders (monogenic) because of its even distribution across the human genome, suited for linkage studies used to identify the responsible gene and smooth sailing PCR (Gray et al. 2000 and Dove. 2007). Gradually, the need to research complex disorders, such as, diabetes, cancer, etc, has switched the favour back to SNPs. Further, the growing interest within the community to research drug responses has also fuelled the urge to utilise SNPs. The focal reason being SNPs have been reported (Gray et al. 2000) to have low mutation occurrences, thus, a strong tool in medical diagnostics and research.

Such is the ever gaining popularity of SNPs, that a world – wide debate sparked involving the number of SNPs required for whole – genome research. The number reportedly fell from a million to 300,000 (Lai et al. 2002). The scientific community is heavily voting for cementing haplotype maps to boost information and cutting down the quantity of SNPs for whole – genome mapping (Uppsala Universitet. Molecular Medicine).

Haplotype based SNP maps will benefit pharmacogenetics in performing comparatively less expensive clinical trials and an effective drug market with ready availability of medicines for individuals in acute risk (Lai et al. 2002).

Sequence repeats are of huge importance as it offers genomic landmark to medical genetics. It has fuelled heavy weight research because of its importance as genetic markers in mapping genes in a successful venture to understand hereditary diseases.

2.0 The tools

2.1 Microsatellites…

Medical genetics research and diagnosis.

Studies conducted on prenatal diagnosis using microsatellites in families with recessive inheritable disorders are an attractive feature. Day et al in 1996 and Lako et al in 1999 worked on 21 hydroxylase deficient families. It is been reported that the disorder arises from mutations in the CYP21 gene. The research reveals that the responsible gene along with a pseudogene is located on a tandemly duplicated section of the DNA in class III HLA region. A reported five microsatellites (found in the HLA III region) have been used in this study. The allelic segregation by microsatellite typing corresponds to the differentiation of mutations in the responsible gene. For a given mutation, the CVS sample and sample of previously affected child exhibit homozygosity while both parents are heterozygous carriers of the same mutation. The research concludes that, with samples available from previous affected child, prenatal diagnosis (PND) using informative markers can be carried out.

Further conclusions state that with respect to PND, microsatellite typing should be used to assist CYP21 genotyping to avoid any irregularities with mutation (Day et al. 1996).

Table 1. Relationship of microsatellite haplotypes with CFTR mutations. (Hughes et al. 1996)

Eftedal et al in 2001 conducted an interesting study using fluorescent polymerase chain reaction (fPCR) on informative microsatellite markers as a “tool” in preimplantation genetic diagnosis (PGD) of cystic fibrosis. In this study PGD was conducted using fPCR of an informative CFTR (cystic fibrosis transmembrane conductance regulator) microsatellite marker on two couples who are compound heterozygotes for cystic fibrosis mutations. Both couples have children. Using informative microsatellite markers two separate alleles are always reportedly observed, even if the embryo genotype is unknown. Embryo biopsy and PCR resulted in transfer of single heterozygote carrier embryo, but these transfers did not lead to term. This research has helped in ruling out the requirement of single cell multiplex PCR for detection of cystic fibrosis compound heterozygotes. Single cell analysis is susceptible to contamination with exogenous DNA. An advantage of the technique is that the heterozygosity of the microsatellite marker helps in identification of contamination with exogenous DNA as it will show alleles different in size in comparison to parental information. So, polymorphic markers can help to realise chances of misdiagnosis.

The investigators (Eftedal et al. 2001) have also reportedly used linked microsatellites in PGD for myotic dystrophy (triplet expansion disease) to minimise the chances of wrong diagnosis when the parents when parents were carrier of similar normal alleles.

Microsatellite tests with fPCR are being used to analyse blood samples of donor and patient, prior to bone marrow transplantation. Quantitative PCR of microsatellite marker is executed after transplantation to determine percentage of patient and donor DNA present. 100% DNA is total engraftment (Peninsula Molecular Genetics Laboratory).

Hughes et al in 1996 used intragenic CFTR microsatellite markers to study mutations in a large number of CF families. He concluded that a set of three haplotypes relate to a bulk (79%) of the delF508 allele (Table 1).

Carney complex is an autosomal dominant syndrome, and recently the responsible gene has been discovered in the long arm of chromosome seventeen – 17q2 (Goldstein et al. 1999). The research focussed on an individual who was in the beginning not suspected of being affected. Genotypic analysis with 17q2 microsatellites revealed that the individual was actually affected. The researchers comment that clinical test is not sufficient to diagnose Carney complex, and it must be coupled with molecular (microsatellite marker) techniques.

Rubinstein – Taybi syndrome (RSTS) is a congenital disorder accompanied by growth and mental retardation. RSTS is caused by chromosomal rearrangement and point mutation of CREB – binding protein gene (CREBBP). Studies involving mutation analysis of CREBBP with intragenic microsatellite markers and fluorescence in – situ hybridisation (FISH) revealed a higher rate of mutation and microdeletion rates in comparison to previously reported works (Bentivegna et al. 2006).

Cancer research involves microsatellite instability (MSI) and it’s being used to discover mismatch repair germline mutation in individuals with colorectal cancer. Tumour MSI examination is the first screening technique used in primary and metastasis tumour. Certain microsatellite markers, BAT26 (Chialina et al. 2006 and Lamberti et al. 1999), are efficient in detecting MSI. The researchers conclude that a small number of microsatellite markers might evolve as the standard test for colorectal cancer (Lamberti et al. 1999). The extensive research enabled the screening of hereditary non-polyposis colon cancer with the designated set of microsatellites before DNA sequencing of the obligate carrier (Chialina et al. 2006).


X – chromosomal STRs (Figure 5) have been successfully used in forensic studies to solve paternity issues, cases involving blood relations, maternity cases, and rape tests. Trimeric, tetrameric and pentameric microsatellites are being used in forensic research. For maternity issues, mitochondrial DNA tests prove expensive. ChrX – STR typing proves to be an economical and easier option. ChrX markers are rarely being used in forensics, but the growing paternity issues in the modern world might boost this technique to popular charts (Szibor et al. 2003).

Figure 5. Position of ChrX STRs used in forensic practice. (Szibor et al. 2003)

Forensic research has also revealed that PCR based STR analysis is effective in identifying human body and related cases with tissue samples even when the samples are in advanced stages of decomposition (Hoff – Olsen et al. 2001).

Human population studies.

Autosomal microsatellites have been used effectively for studying diversity in humans and creating related databases. Population genetics studies on certain ethnical communities of India have shown highly informative polymorphisms in selected microsatellites (PCR based STR typing) which prove the communities to be diverse in a huge population count of the country (Bindu et al. 2005).

2.2 SNPs …

SNP markers enable feasibility of analysing the relationship between the phenotype and the responsible genes (Gray et al. 2000). This is one the critical reasons why SNPs have been selected for constructing high – density genetic marker maps in modern human genetic research (Nielsen et al. 2005). SNP based association studies involve direct analysis of SNP for relationship with disease, and, utilising SNP markers for linkage disequilibrium (it is the calculation of the degree of association between two gene markers and used to identify those regions of the genome related to disease in a population). By understanding the recombination patterns in genomes, it will help in spreading the SNP markers so as to reduce amount of markers needed for gene scans (Gray et al. 2000). Figure 6.

Figure 6. Genome wide association scan. (a) Gene rich regions are selected for marker saturation (genes represented by vertical lines and markers are represented by arrows). (b) Within those gene rich intervals, recombination hotspots (circles) define haplotypes and govern required marker density. Regions with more hot spots require larger number of markers. (Gray et al. 2000)

SNP is identified by firstly discovering single strand conformation polymorphisms, followed by heteroduplex analysis (heteroduplex detection is done by differential retention on a high – performance liquid chromatography column) and finally DNA sequencing. SNP typing techniques used are hybridisation, primer extension, and cleavage techniques.

Scanning for complex diseases are of great enthusiasm. SNP mapping has been carried out for late onset Alzheimer disease (AD). APOE is the culprit gene for the disease. Martin et al in 2000 used sixty SNPs within the APOE that was analysed in unrelated AD patients and AD families. The work illustrates that association with AD can be realised when SNPs are carefully chosen. Interestingly, SNP genotyping was conducted in the G72 gene of schizophrenic individuals. The primary SNP which had association with schizophrenia (G72) also shared an association with bipolar affective disorder (BPAD). SNP genotyping helped in establishing that the two psychiatric disorders shared common traits (Schumacher et al. 2004). Recent research has revealed 1q23.3 is a responsible centre for schizophrenia. Association has been elucidated with three microsatellites and a couple of SNPs in the said locus (Puria et al. 2007).

Certain research groups have stated that SNPs can be extensively used to identify the susceptible genes for asthma. Linkage analysis to understand the genetics of asthma as a complex disease which does not follow the Mendelian pattern has not been a success. It has been observed that linkage works have not proved potent enough to realise disease causing genes. PCR and restriction enzyme site based detection of SNPs for asthma have been thoroughly discussed (Palmer et al. 2001).

Mechanisms of genes responsible for autoimmune diseases using SNPs have been looked into. Polymorphisms of a T – lymphocyte regulatory gene, CTLA4 have been investigated. Some examples of autoimmune disorders are type I diabetes and Grave’s disease. Association with CTLA4 SNPs and a large spectrum of type I diabetes and Grave’s patients have been discovered. Furthermore, SNP typing has revealed these disorders are closely related (Ueda et al. 2003). Inteferons (IFN) are chemicals secreted by the immune system in response to viral particles. Hypersecretion of IFN is a symptom of an autoimmune disease, systemic lupus erythematosus (SLE). Genotyping the culprit genes using SNPs in the IFN system has revealed TYK2 and IRF5 genes in having association with SLE (Uppsala Universitet. Molecular medicine).

Bone marrow transplantation (BMT) is the best therapy for people suffering from haematopoietic malignancies. The ratio of the donor and recipient cells is critical in understanding the success of the transplant. A quantitative PCR technique has been developed analysing the presence of SNPs to measure the proportion of donor and recipient cells (Harries et al. 2005). Further research has revealed 13q deletions are a regular feature in these malignancies. PCR based digital SNP (dSNP) techniques are being developed to detect the deletions as a predictive diagnosis (Peninsula Molecular Genetics Laboratory).

SNPs located in the coding region of the genome control gene expression and cause diversity in human races. Using a pair of SNPs in the same gene to identify cis – acting haplotypes has showed promise. This technique is being used on Nordic children suffering from acute leukaemia. The research concentrates on creating a genetic database to predict drug response in children with acute leukaemia (Uppsala Universitet. Molecular medicine).

Population genetics related work has been employed to elucidate genes responsible for fetus growth, and primarily birth weight factors. In order to narrow in on the genes that affect birth weight, researchers are going for extensive genome search using 250,000 SNP markers (Uppsala Universitet. Molecular medicine).

SNPs useful in genetic study are normally heterozygous, so, their collection proves valuable for creating databases for human population research. A technique has been developed to do just that: PCR products are fluorescently labelled and electrophoretically separated using DNA sequencer. SNP alleles are detected as separated peaks in the electrophoresis. It has also been demonstrated that utilising this technique, SNP alleles have been quantitatively detected from a mixture of DNA samples. A wide range of SNP frequencies have been reportedly elucidated from an array of ethnic backgrounds (Hayashi. 2001).

“Elimination of variation in regions linked to beneficial mutation is known as selective sweep”. Selective sweeps are important as it holds the key to human evolution, and connection to complex disease genes. A complete genome scan for these regions is an uphill task primarily because bulk of the data is composed of SNP genotypes. Its detection has been demonstrated from genomic SNP data (Nielsen et al. 2005).

3.0 Conclusion

Current works have revealed that certain SNPs produce premature termination codons which change the structure of the proteins (Savas et al. 2006). This has fuelled the research of such SNPs as it casts new light on medical importance. SNP data has also been used to discover deletions (McCarroll et al. 2006) throughout the human genome.

In the commercial world, manufacturers are ever striving to make SNPs on arrays more informative. Scientists conducting research on families or population are screening for SNPs in thousands of individuals. Biotechnology firms are readily catering to the growing demand of the medical genetics community. As discussed earlier, microsatellites were the choice markers used in analysis of monogenic diseases and extensive linkage studies. As microsatellites are unevenly distributed along the human genome it takes ages to reach the precise locus. Ann Christine Syvanen, research group leader at SNP Technology Platform, Uppsala University rightly says that researchers are pursuing linkage studies with microsatellites as they are highly informative. The drawback being, it’s hard to genotype them. Comparative linkage analysis studies using microsatellites and SNPs have revealed contradictory results. Linkage results from SNPs were stronger when compared to microsatellites. This was credited to the dense SNP maps in contrast to microsatellite maps available for quantitative traits (Tayo et al. 2005).

However, some workers have observed that even though SNP research has the potential to produce “tailor – made” drugs and relatively simple tests to elucidate an individual’s risk to certain diseases, such end results are a tougher nut to crack than previously expected (Roberts. 2000).

Inspite that, researchers have developed interactive visualisation software (SNP – VISTA). This is to aid scientists in analysing disease causing genes for association with SNPs and discovery of additional alleles (Shah et al. 2005). Such programmes to detect and map SNPs enhance the understanding of the human genome sequence (Bentley. 2000).

It was previously thought that BCL2 gene is responsible for SLE as the gene is responsible for other autoimmune disorders and its mutation detected in SLE individuals. However, with the combined use of microsatellite marker and SNPs located within the gene, such a hypothesis was ruled out (Johansson et al. 2000). Certain mental retardation syndromes (Hampshire et al. 2006) have also been tracked using both microsatellite markers and SNPs located in susceptible genes.

There’s an estimated 500,000 SNPs in the coding region which is approximately 6 per gene (Collins et al. 1998). This makes them popular. They are more concrete, numerous, easier to detect when compared to microsatellites. SNP typing is a power “tool” for the future of medical diagnostics and research. With immense investments being made by pharmaceutical firms and massive government based projects constructing SNP databases (The Sanger Institute) for disease tracking, its one machine which is here to stay and ramify.


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