Genetic Variation and Alleles

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Questions and Answers

What is the frequency of alleles referred to as polymorphisms?

Less than 0.1%

Less than 5%

Greater than 1% (correct)

Exactly 0.5%

What is the term for different versions of a locus?

Haplotypes

Variants

Alleles (correct)

Genotypes

Why do nearby alleles tend to be inherited together?

Because they are on the same chromosome

Because they are on the same chromosome arm

Because they are linked by meiotic recombination

Because chromosomes are very large and crossovers are rare (correct)

What is the term for a group of alleles inherited from a single parent on the same chromosome homologue?

Haplotype Signup and view all the answers

What is the frequency of SNVs (Single Nucleotide Variants) in the human genome?

One every 1kb Signup and view all the answers

What is the main reason why SNVs are often analyzed in genetic studies?

They are common and easy to assay Signup and view all the answers

What type of genetic variant was widely used in genetic studies before 2010?

Short tandem repeats Signup and view all the answers

In which field is the short tandem repeat type of genetic variant still used today?

Forensic science Signup and view all the answers

What phenomenon allows a harmful allele to increase in frequency in a population?

Balancing selection Signup and view all the answers

Why does the sickle cell anaemia allele HbS increase in frequency in certain areas of Africa?

It grants resistance to malaria in carriers Signup and view all the answers

What is the distribution pattern of sequence variation across the human genome?

Higher frequency in non-coding regions Signup and view all the answers

Which type of trait involves many genes and can also be influenced by environmental factors?

Complex traits Signup and view all the answers

Which of the following diseases is an example of a single gene disorder?

Cystic Fibrosis Signup and view all the answers

How do variants in exons typically compare to those in non-coding regions in terms of potential impact?

More likely to affect gene function Signup and view all the answers

What is the outcome of random mating according to the Hardy-Weinberg Law?

Genotype frequencies that are a simple function of allele frequencies Signup and view all the answers

Which of the following is necessary for a population to be in Hardy-Weinberg Equilibrium?

Random mating Signup and view all the answers

What is the frequency of heterozygous genotype (Aa) for a biallelic gene in a population?

2pq Signup and view all the answers

Why might the Hardy-Weinberg Law be disrupted in certain populations?

Small population sizes Signup and view all the answers

Which factor can cause a population bottleneck, affecting genetic variation?

Reduced population size Signup and view all the answers

What does the Hardy-Weinberg equation predict for allele frequencies in a stable population over generations?

They will remain constant Signup and view all the answers

Which scenario could lead to genetic drift in a population?

Random fluctuations in a very small population Signup and view all the answers

What does purifying (negative) selection do to allele frequencies?

Decreases the frequency of harmful alleles Signup and view all the answers

When a population experiences a founder effect, what typically happens?

A small subset migrates, reducing genetic variation Signup and view all the answers

How can allele frequencies be deduced within a population in Hardy-Weinberg Equilibrium?

By calculating from genotype frequencies Signup and view all the answers

What is the primary focus of WGS and WES in disease research?

Rare disease and cancer Signup and view all the answers

What is the purpose of large projects like UK Biobank?

To identify the underlying genetic basis of common complex disease Signup and view all the answers

How are the causal variants/alleles characterized in monogenic disorders?

Rare and with strong, detrimental effects Signup and view all the answers

What is the challenge in identifying predisposing variants in common complex disease?

They are rare and require very large sample sizes to detect Signup and view all the answers

What is the Online Mendelian Inheritance in Man (OMIM) database?

A database of genetic disorders and genetic phenotypes Signup and view all the answers

What type of disease is often studied using family-based linkage studies?

Monogenic disorder Signup and view all the answers

What is a characteristic of common complex disease?

Variants have modest effects and are relatively common Signup and view all the answers

What is a consideration in large-scale genetic studies?

All of the above Signup and view all the answers

What is the main purpose of genetic linkage studies?

To find genes associated with single gene disorders Signup and view all the answers

In the provided example, what indicates the presence of a causal mutation?

An 'X' on the red chromosome segment Signup and view all the answers

What do the unshaded bars represent in the pedigree example?

Additional copies of the chromosome from spouses marrying into the pedigree Signup and view all the answers

What process causes recombination events that break up chromosome segments?

Meiosis Signup and view all the answers

How do polymorphic loci act in genetic linkage studies?

As tags Signup and view all the answers

Why is sequencing required even after identifying a chromosomal region linked to a trait?

To identify the precise gene and causal mutation responsible Signup and view all the answers

What does the term 'haplotype' refer to in the context of the example?

A cluster of alleles at polymorphic loci on the same homologue Signup and view all the answers

What challenge is often faced when a chromosomal region linked to a trait is identified?

The chromosomal region identified may encompass many genes Signup and view all the answers

What is one of the reasons whole genome sequencing remains challenging?

Storing and analyzing the vast amounts of data is computationally expensive. Signup and view all the answers

Why have genetic linkage studies been more successful in identifying genes for monogenic disorders compared to common complex diseases?

Monogenic disorders typically have high penetrance and predictable inheritance patterns. Signup and view all the answers

What type of genetic study is exemplified by the Deciphering Developmental Disorders (DDD) Study?

Whole Exome Sequencing (WES) Signup and view all the answers

In the context of genetic studies, what does the term 'concordance rate' refer to?

The percentage of cases where both twins in a pair share a trait. Signup and view all the answers

Why is it difficult to identify genes underlying common complex diseases?

Many genes and environmental factors contribute to these diseases. Signup and view all the answers

According to twin studies, which of the following diseases shows a stronger genetic contribution?

Schizophrenia Signup and view all the answers

What is a major advantage of whole exome sequencing (WES) over whole genome sequencing (WGS)?

WES is less computationally intensive because it focuses on protein-coding regions. Signup and view all the answers

In genetic studies, what does the term 'penetrance' refer to?

The probability that a person with a particular genotype will exhibit the associated phenotype. Signup and view all the answers

What challenge is associated with the phenotypes of common complex diseases?

They often have multiple subtypes which are hard to classify. Signup and view all the answers

What information can comparisons between identical (monozygotic) and non-identical (dizygotic) twins provide?

The proportion of genetic versus environmental contribution to a trait. Signup and view all the answers

What is the primary purpose of a genome-wide association study (GWAS)?

To scan the genome for regions contributing to complex phenotypes Signup and view all the answers

What type of genetic variation is commonly assayed in GWAS?

Single Nucleotide Polymorphisms (SNPs) Signup and view all the answers

Why is a large number of individuals required in GWAS studies?

Because complex traits are often influenced by many variants with small effects Signup and view all the answers

What does a Manhattan plot show in the context of GWAS?

The statistical significance of each SNP's association with a trait Signup and view all the answers

Which technology is used to genotype an individual's genomic DNA for thousands of SNP loci simultaneously?

SNP microarrays Signup and view all the answers

What is one of the main reasons why many SNPs are biallelic?

Because they are ancient benign mutations that spread through the population Signup and view all the answers

What makes identifying the causal variant in a GWAS challenging?

The associated SNP may only mark the chromosomal segment containing the variant Signup and view all the answers

Why is Whole Genome Sequencing (WGS) not yet common for very large scale GWAS studies?

It is still very expensive Signup and view all the answers

Which diseases have been studied using GWAS to uncover contributing genes?

Type 1 and Type 2 Diabetes, Rheumatoid arthritis, and Crohn’s disease Signup and view all the answers

Which statement is true regarding the resolution and cost trade-off in genome analysis technologies?

WGS offers high resolution but is expensive Signup and view all the answers

Study Notes

Genetic Variation

Individual genomes differ at a small fraction of bases, but due to the large size of genomes, there are millions of differences between individuals.
Each individual carries both rare and common variants.
Alleles are different versions of a locus, and variants that arise within the germline can be inherited.
Rare variants may be unique to an individual or shared with relatives in a family, and often have arisen in recent generations.
Common variants are shared with many others in a population, often having no/little effect on phenotype, and arose many generations ago, spreading through the population.

Types of Genetic Variation

Single Nucleotide Variants (SNVs) or Single Nucleotide Polymorphisms (SNPs) are the most commonly analyzed type of genetic variation.
SNPs occur frequently (~1 every 1kb in the human genome) and are easy to assay.
Other types of genetic variation include short tandem repeats (also known as microsatellites), which are still used in forensics for DNA fingerprinting.

Hardy-Weinberg Law and Allele Frequencies

The Hardy-Weinberg Law is a mathematical relationship between allele and genotype frequencies in an idealized population.
Random mating results in genotype frequencies that are a simple function of allele frequencies.
The law states that p² + 2pq + q² = 1, where p and q are the frequencies of two alleles in a biallelic gene.
Allele frequencies can be deduced from genotype frequencies in the same generation.
Genotype frequencies can be computed from allele frequencies if the population is in Hardy-Weinberg Equilibrium (HWE).

Applications of Hardy-Weinberg Law

The HW equation is often used in clinical situations to calculate the frequency of carriers of autosomal recessive disorders.
However, Hardy-Weinberg equilibrium can be disrupted by non-random mating, population bottlenecks, founder effects, and genetic drift.

Genetic Variation and Disease

Single gene disorders are individually rare, but have a strong genetic component, and are often caused by mutations in a single gene.
Complex traits involve many genes and environmental factors, and are more common.
Variants occurring within exons are more likely to affect the function of a gene product and be real mutations.
Variants outside exons are more likely to be neutral variants.

Genetic Linkage Studies

Genetic linkage studies follow the inheritance of a trait in an affected family (pedigree) and look for co-segregation of the phenotype with alleles of polymorphic genetic loci from across the genome.
The approach identifies a chromosomal segment that appears to be present in those with the trait.
The alleles at polymorphic loci act as tags allowing the inheritance of chromosomal segments to be tracked through the pedigree.
This approach points to a segment of the genome where the gene underlying the phenotype is likely to be.

Limitations of Genetic Linkage Studies

The chromosomal region identified by genetic linkage studies is often quite large (many Mbps) and may encompass many genes.
Sequencing is required to identify the causal mutation and gene responsible.

Historical Importance of Genetic Linkage Studies

Genetic linkage studies have been a powerful way of identifying genes underlying disorders caused by a genotype at a single locus that has high penetrance and a predictable inheritance pattern in families (Mendelian inheritance).

Challenges of Identifying Genes Underlying Common Complex Traits

Common complex diseases have a major impact on health and form the bulk of the disease burden in industrialized societies.
Identifying genes underlying common complex diseases is challenging because many genes contribute to individual predisposition to the phenotype, with most genetic variants contributing in only a small way.
The phenotype is often hard to classify, with many subtypes and no straightforward pattern of inheritance is seen.
Environmental factors also influence the trait.

Twin Studies

Twin studies are used to quantify the extent of genetic and environmental contributions to a trait.
The concordance rate for monozygotic twins is higher than for dizygotic twins.
The higher the concordance rate, the more important the genetic contribution.

Genome-Wide Association Studies (GWAS)

GWAS is an alternative to family/pedigree-based linkage studies.
The approach looks for genetic variants shared by “unrelated” people with a trait/disease.
The logic behind this approach is that many genetic variants can each increase susceptibility to a particular trait to a small extent.
These variants are themselves quite benign and can persist and spread in the population, over many generations.
The type of genetic variation assayed in such studies is the SNP (Single Nucleotide Polymorphism).

GWAS Data Analysis

GWAS data is presented in the form of “Manhattan plots”, where the x-axis shows the chromosomal location of each SNP, and the y-axis shows the statistical significance of the association of each SNP with the particular trait.
The green peaks in the plots represent SNPs that show significance values above the threshold.

Limitations of GWAS

Once associated SNPs have been identified by GWAS, the causal variant then needs to be pinpointed, which can be challenging.
Many SNPs lie outside protein-coding genes, in regions of the genome with no known function.

Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES)

WGS and WES are approaches that allow all the genetic variation in a genome to be assayed – the highest resolution possible.
However, because of the expense, this approach is not yet common for very large scale studies.
There is a trade-off between cost and the amount of genetic variation you can sample.

Large-Scale Projects

Large-scale projects, such as the UK Biobank, hold great promise for identifying the underlying genetic basis of common complex disease.
These projects are resource-intensive but are long-term investments that are generating growing datasets.
Issues of secure data storage, anonymity of data generated, and the ethics of sampling are carefully considered.

Online Mendelian Inheritance in Man (OMIM) Database

OMIM is a comprehensive compendium of human genes and genetic phenotypes, updated daily.
OMIM contains information on all known monogenic disorders, on over 15,000 genes, and a rapidly growing number of genes associated with susceptibility to common complex disease.

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Description

This quiz covers genetic variation, alleles, and rare variants, as discussed in Lecture 2 of the genetics block. It explores the different types of genetic variation, how they arise, and their inheritance.