Theme 5 Module 3

Why can’t geneticists study inheritance in humans the same way Mendel studied pea plants?

Back (Answer):

• Mendel used pea plants because they:

  • Produce many offspring

  • Can be bred on purpose to observe traits

• Studying humans is more difficult because:

  • Humans have few offspring

  • It is unethical to ask people to breed for experiments

• To overcome these limits, geneticists:

  • Study family history

  • Create a pedigree (family tree)

• Pedigrees allow scientists to:

  • Visually track traits across generations

  • Study inheritance patterns without unethical experiments

What do the symbols and lines in a pedigree represent? what are pedigrees for?

Back (Answer):

• Symbols:

  • Square = Male

  • Circle = Female

  • Shaded symbol = Individual affected by the trait/disease

• Relationships:

  • One horizontal line = Mating between unrelated individuals

  • Two horizontal lines = Mating between related individuals

• Offspring (progeny):

  • Shown below the parents

  • Arranged left to right in order of birth

• Purpose of pedigrees:

  • Track how traits are passed down

  • Identify dominant and recessive inheritance patterns

  • Observe the same inheritance rules Mendel found in pea plants

  • Pedigrees are visual tools that show how traits are inherited in families.

What is the structure of the human genome in terms of chromosomes, DNA, and genes?

Back (Answer):

• Human cells contain 23 pairs of chromosomes

• These chromosomes together contain over 3 billion base pairs of DNA

• After sequencing the human genome, scientists discovered:

  • More than 20,000 protein‑coding genes

  • Additional genes that code for functional RNA molecules

• This means:

  • Each chromosome must contain many genes

  • There is not just one gene per chromosome

🧠 Key idea to remember:
Humans have many genes spread across 23 chromosome pairs.

Are all genes on the same chromosome always inherited together?

Back (Answer):

• Mendelian inheritance explains basic dominant and recessive traits

• However, because chromosomes have many genes, inheritance is more complex

• Important question:

  • Are all alleles on the same chromosome inherited as one fixed unit?

• Observations show:

  • Plants and animals display many different trait combinations

• This means:

  • Alleles on the same chromosome can separate

  • They can recombine into new combinations

• Therefore:

  • Genes that are physically linked can become unlinked through recombination

🧠 Key idea to remember:
Linked genes can recombine, creating genetic variation beyond simple Mendelian rules.

How do sex chromosomes determine biological sex in humans?

Back (Answer):

• Humans and other mammals have two sex chromosomes:

  • X chromosome

  • Y chromosome (much smaller than X)

• Females (XX):

  • Carry two X chromosomes

  • One X inherited from each parent

• Males (XY):

  • Develop from a gamete with one X and one Y chromosome

• Even though males and females differ anatomically and physiologically,

  • The chromosomal basis of sex determination is unique

🧠 Key idea to remember:
XX = female, XY = male; Y chromosome triggers male development.

How are the X and Y chromosomes different in terms of genes and inheritance?

Back (Answer):

• Most regions of the X and Y chromosomes are non‑homologous

  • They do not share matching genes

  • Therefore, recombination usually does not occur

• Only small regions at the tips of X and Y:

  • Allow pairing and proper segregation during meiosis

• Y chromosome:

  • Contains 78 genes

  • Codes for about 25 proteins

  • About half of these genes are involved in sex determination

• X chromosome:

  • Contains about 1100 genes

  • Most genes have functions unrelated to sex

• A gene located on the X or Y chromosome is called a sex‑linked gene

  • Expression of the trait may depend on the sex of the individual

🧠 Key idea to remember:
X has many genes, Y has few; sex‑linked traits depend on sex.

How is red/green colour‑blindness inherited in humans?

Back (Answer):

• Red/green colour‑blindness is:

  • A recessive

  • X‑linked trait

  • Caused by a gene located on the X chromosome

• Scientists track this inheritance using human pedigrees:

  • Follow traits from grandparents → parents → children

  • Can span multiple generations

• Testing method: Ishihara colour test

  • Made of circles with coloured dots

  • Dots form numbers (e.g., 5)

  • Clearly visible to people with normal colour vision

  • Hard or impossible to see for colour‑blind individuals

🧠 Key idea to remember:
Red/green colour‑blindness is a recessive X‑linked disorder tracked using pedigrees and tested with Ishihara plates.

Why does X‑linked colour‑blindness affect males more often than females?

Back (Answer):

• Females (XX):

  • Must be homozygous recessive to be colour‑blind

  • Heterozygous females are carriers

  • Carriers do not show the phenotype

  • Can pass the allele to their children

• Males (XY):

  • Have only one X chromosome

  • If they inherit the recessive allele from their mother,

    • They will be colour‑blind

• Males are called hemizygous:

  • Only one allele at the X‑linked locus

  • No second allele to mask its effect

• In hemizygous individuals:

  • Rules of dominance vs. recessiveness do not apply

  • The single allele is always expressed

🧠 Key idea to remember:
Males are hemizygous for X‑linked genes, so one recessive allele is enough to show the trait.

What is the probability of passing on the colour‑blindness allele from a carrier female?

Back (Answer):

• Colour‑blindness follows Mendelian inheritance

• A carrier female has:

  • One normal X chromosome

  • One X chromosome with the affected (colour‑blindness) allele

• Because the trait is recessive:

  • She is not colour‑blind

  • She carries the allele

• Each child has:

  • 50% chance of inheriting the affected allele

  • 50% chance of inheriting the normal allele

• This 50% chance applies to all offspring, regardless of sex

🧠 Key idea to remember:
Carrier mothers pass the affected X allele to half of their children.

How does inheriting the colour‑blindness allele affect male vs. female offspring?

Back (Answer):

• Males (XY):

  • Are hemizygous for X‑linked genes

  • Show the phenotype of the single X chromosome they receive

  • If they inherit the affected allele → they will be colour‑blind

• Females (XX):

  • Can inherit the affected allele with 50% probability

  • If heterozygous:

    • They will not be colour‑blind

    • They become carriers

• Punnett squares help visualize:

  • Affected males

  • Carrier females

• Dominance rules do not apply in hemizygous males

🧠 Key idea to remember:
Affected X → colour‑blind males; carrier females do not show the trait.

Given the principles of Mendelian inheritance, there

is a 50% chance of passing on the allele that

determines colour-blindness. Consider the case of a

female with one X chromosome having the affected

allele (indicated by the red line in the figure) and one

X chromosome with the normal allele (indicated by

the black line). Because it is a recessive trait, she is

not colour blind but is a carrier for colour-blindness

and there is a 50% chance of her offspring inheriting

either the normal or affected allele. Because males

are hemizygous for genes on the X chromosome, they

will show the phenotype of the X chromosome

received from the mother. Using a Punnett square,

we can see that a male offspring that inherits the

affected allele will be colour blind. Female offspring

can inherit the affected allele, with a 50% probability,

but will not show the phenotype but will again be

carriers of it

How do carrier females contribute to the inheritance of X‑linked recessive traits, and how are they identified in pedigree?

Back (Answer):

• In pedigrees, it is possible to trace females who do not show a phenotype but still carry a recessive allele

• These females are heterozygous:

  • One normal X chromosome

  • One X chromosome carrying the recessive allele

• Because the trait is X‑linked recessive:

  • A single normal allele masks the recessive allele

  • The female does not express the disorder

• Even though they are unaffected, carrier females:

  • Can pass the affected allele to their children

  • Have a 50% chance of passing the recessive allele to each son

• Sons who inherit the affected X chromosome:

  • Are hemizygous

  • Will express the disorder because they have no second X chromosome

• Pedigrees allow scientists to:

  • Track these silent carriers across multiple generations

  • Predict inheritance patterns based on Mendelian principles

Key takeaway:
Carrier females play a critical role in maintaining and transmitting X‑linked recessive traits within families, even when they appear unaffected.

What is haemophilia, and how does it demonstrate X‑linked recessive inheritance through pedigrees?

Back (Answer):

• Haemophilia is a blood‑clotting disorder

• It is caused by:

  • A mutation in a gene that encodes a protein required for normal blood clotting

• This mutation leads to:

  • Inability to clot blood properly

  • Increased risk of excessive or uncontrolled bleeding

• Haemophilia is inherited as an X‑linked recessive trait

• Historical example:

  • Queen Victoria was a carrier of the haemophilia allele

  • She did not show symptoms

  • She had a son affected by haemophilia

• This occurred because:

  • She passed her affected X chromosome to her son

  • The son was hemizygous and expressed the disorder

• In pedigrees:

  • Carrier females are often indicated separately

  • Affected males appear more frequently than affected females

• These inheritance patterns follow:

  • The same Mendelian rules seen with other X‑linked recessive traits, such as colour‑blindness

Key takeaway:
Haemophilia clearly shows how X‑linked recessive disorders can be passed through unaffected carrier females and appear primarily in males.

What does the Punnett square reveal about the inheritance of haemophilia in the children of Queen Victoria and Prince Albert?

Back (Answer):

• Haemophilia is an X‑linked recessive disorder

• Queen Victoria was a carrier for the haemophilia allele:

  • One normal X chromosome

  • One X chromosome with the mutant haemophilia allele

• Prince Albert was unaffected:

  • He carried a normal X chromosome and a Y chromosome

• A Punnett square analysis shows the following outcomes for their children:

  • Female offspring (XX):

    • 50% will inherit the normal X from Queen Victoria and be completely normal

    • 50% will inherit the affected X and be carriers

    • None are expected to be affected

  • Male offspring (XY):

    • 50% will inherit the normal X and be unaffected

    • 50% will inherit the affected X and will have haemophilia

• These ratios follow Mendelian inheritance principles for X‑linked recessive traits

Key takeaway:
When a carrier female mates with an unaffected male, half the sons are affected and half the daughters are carriers.

Front (Question):
Why is haemophilia rare in females, and why is it no longer present in the modern British royal family?

Back (Answer):

• For a female to be affected by haemophilia, she must:

  • Inherit an affected X chromosome from her mother

  • And an affected X chromosome from her father

• This scenario is rare because:

  • Affected males often have reduced survival or reproduction

  • Females are usually carriers, not affected

• Although haemophilia became well known due to its presence in European royal families, it is no longer found in the current British royal line

• This is because:

  • The present royal family descends from King Edward VII

  • King Edward VII was a son of Queen Victoria

  • He was not affected by haemophilia

  • Therefore, he did not carry the mutant allele

• Because he lacked the allele:

  • He could not pass it on to his children

  • The mutant allele was eliminated from that lineage

• This demonstrates how X‑linked recessive alleles can:

  • Persist for generations through carriers

  • Be lost entirely if not transmitted further

Key takeaway:
Haemophilia disappeared from the British royal family because the unaffected male lineage no longer carried the mutant X‑linked allele.

Does Mendel’s second law of independent assortment always apply to all genes?

Back (Answer):

• Mendel’s second law of inheritance states that:

  • Alleles of different genes assort independently during gamete formation

• This law assumes that genes:

  • Are located on different chromosomes, or

  • Are far enough apart on the same chromosome

• This raises an important question:

  • What if two genes are physically located close together on the same chromosome?

• Genes that are physically attached to the same chromosome may:

  • Not assort independently

  • Be inherited together more often than expected

• Such genes are referred to as linked genes

• Therefore:

  • Mendel’s second law is not always true

  • It must be modified to account for gene linkage

Key takeaway:
Independent assortment applies only when genes are not physically linked on the same chromosome.

What evidence shows that some genes on the human X chromosome are linked?

Back (Answer):

• In human females, the two X chromosomes pair during prophase I of meiosis I

• Each X chromosome:

  • Is approximately 155 megabases (155 million base pairs) in length

  • Contains about 1100 genes

• The X chromosome has two regions:

  • p arm (short arm)

  • q arm (long arm)

• Several important genes are located on these arms, including:

  • Dystrophin gene: codes for a protein required for muscle cell development

  • HPRT1 gene: mutations cause severe, recurring acute arthritis

  • Colour‑blindness‑associated genes

  • Haemophilia‑associated genes

• Genes located close together on the same chromosome:

  • Are called linked genes

  • Tend to be inherited together

  • Do not segregate independently during meiosis

• Colour‑blindness and haemophilia genes are an example of linked genes on the X chromosome

• This leads to the final question:

  • Will linked genes always be inherited together, or can they sometimes be separated?

Key takeaway:
Genes that are close together on the same chromosome are linked and tend to be inherited together, challenging Mendel’s second law

Will linked genes always be inherited together during meiosis?

No. Linked genes will not always be inherited together. In fact, the linkage can be broken. In prophase of meiosis, all homologous chromosome pairs line up beside each other and form chiasmata or crossovers. It is here that the linkage between neighbouring genes on a chromosome is broken. When alleles of neighbouring linked genes are separated from each other during recombination events in meiosis I during gamete formation, it is possible to see that what were once linked genes are inherited independently in subsequent offspring. As a result, some offspring may inherit only one of the genes due to these recombination events that occur between linked gene

Back (Answer):

• No, linked genes are not always inherited together

• Although linked genes are located close to each other on the same chromosome and tend to be inherited together:

  • Their linkage can be broken

• This breaking of linkage occurs during meiosis, specifically:

  • Prophase I of meiosis I

• During prophase I:

  • Homologous chromosomes pair up along their length

  • They form structures called chiasmata (points of crossing over)

• At these chiasmata:

  • Physical exchanges of DNA occur between homologous chromosomes

• These exchanges can separate alleles of genes that were previously linked

Key takeaway:
Gene linkage is not permanent; it can be disrupted by crossing over during meiosis.

How does recombination break gene linkage and change inheritance patterns?

Back (Answer):

• Crossing over occurs during prophase I of meiosis

• At this stage:

  • Homologous chromosomes exchange corresponding DNA segments

• When a crossover occurs between two linked genes:

  • The alleles of those genes can be separated

  • This process is called genetic recombination

• As a result:

  • Alleles that were previously inherited together may now be distributed into different gametes

• This can lead to offspring that:

  • Inherit only one of the linked genes

  • Show inheritance patterns that resemble independent assortment

• Therefore:

  • Linked genes can sometimes behave as if they are not linked, depending on where recombination occurs

Key takeaway:
Recombination during meiosis can separate linked genes, allowing them to be inherited independently in some offspring.

How does recombination affect linked genes, and why does the distance between genes matter?

Back (Answer):

• During recombination, the physical position of genes on the chromosome does not change

• What changes is:

  • The association of alleles carried on each chromatid

• If two linked genes are far enough apart on a chromosome:

  • A crossover occurring between them can separate their alleles

  • This produces recombinant chromatids with new allele combinations

• If two linked genes are very close together or immediately adjacent:

  • Crossovers are unlikely to occur in the region between them

  • Even if crossing over occurs elsewhere on the chromosome, it will not separate these genes

• As a result:

  • Closely linked genes show little or no recombination

  • More distant linked genes show higher recombination frequency

Key takeaway:
The farther apart two genes are on a chromosome, the more likely recombination will separate their alleles.

How does crossing over generate recombinant allele combinations using genes A and B as an example?

Back (Answer):

• Consider two homologous chromosomes carrying genes A and B:

  • One chromosome has A B

  • The homologous chromosome has a b

• These original allele arrangements are called parental (non‑recombinant) combinations

• If a crossover occurs between genes A and B during meiosis I:

  • Alleles are exchanged between homologous chromatids

• This produces four possible gamete types:

  • Parental (non‑recombinant):

    • A B

    • a b

  • Recombinant:

    • A b

    • a B

• If genes A and B are very close together:

  • Crossovers are unlikely to occur between them

  • Recombinant gametes are rare or absent

  • Only parental combinations are usually produced

• This principle allows geneticists to:

  • Use recombination frequency as a tool

  • Estimate the distance between genes on the same chromosome

• Genes with low recombination frequency are close together

• Genes with high recombination frequency are farther apart

Key takeaway:
Recombination frequency reflects gene distance and can be used to map genes along a chromosome.

During recombination of alleles, the position of genes

does not change, but the relative association of

alleles does. If the linked genes are far enough apart,

recombinant chromatids that carry alternate allele

combinations are generated during crossover events.

Consider the case of this sample set of two genes (A

and B), and the two homologous chromosomes that

carry different alleles of them. The chromosome from

one parent has big A big B and the chromosome from

the other parent has little a and little b. In the event

of a crossover occurring in the region between these

two genes the illustrated crossover would create the

recombinant gametes containing big A, little b and

little a, big B in addition to the parental non-

recombinant big A, big A and little b, little b allele

combinations. However, if the linked genes are

immediately adjacent to each other with very little

distance in between, there would be no crossing over

during meiosis I or any crossovers that did occur

would not be in the region between these two genes.

As a result, there would be no recombination of

alleles, and we would expect little or no cross-over

between these two genes, although a crossover is still

possible in other regions of the chromosomes. What

can we do with this information? Since the

recombination between linked genes is dependent on

the distance between them, genes that are closer

together show less recombination frequency than

genes that are located far apart from each other.

Recombination frequency is a convenient tool that

can be used to determine the distance between

genes along the same chromosome

How does this pedigree demonstrate linkage and recombination between the colour‑blindness and haemophilia genes?

Back (Answer):

• Genes that are in close proximity on the same chromosome tend to be inherited together

• In this pedigree:

  • The inheritance of colour‑blindness and haemophilia generally occurs together

  • This indicates that the genes for these traits are linked on the X chromosome

• Based on linkage:

  • If a person inherits one trait, they are expected to inherit the other

• An important exception is observed:

  • An individual in generation IV has only haemophilia, not colour‑blindness

• This outcome is unexpected because:

  • The individual’s mother was a carrier for both traits

  • Linkage would predict inheritance of both alleles together

• The separation of these traits is explained by:

  • Crossing over (recombination) during meiosis

  • A crossover occurred between the haemophilia and colour‑blindness genes

• This recombination event separated the alleles, allowing:

  • One gene to be inherited without the other

Key takeaway:
Pedigrees can reveal rare recombination events where linked genes are separated by crossing over.

How does recombination frequency allow scientists to determine gene distance and create linkage maps?

Back (Answer):

• Recombination frequency measures how often linked genes are separated by crossing over

• Individuals with unexpected trait combinations:

  • Are called recombinant individuals

  • Indicate that recombination has occurred between linked genes

• The frequency of these recombinant individuals:

  • Reflects the distance between genes

  • Higher frequency means genes are farther apart

  • Lower frequency means genes are closer together

• This information allows researchers to construct a linkage map

• A linkage map:

  • Shows the relative distance between genes on a chromosome

  • Shows the order of genes along the chromosome

• Analysis of this pedigree, along with many others, shows that:

  • The colour‑blindness and haemophilia genes are approximately 12 map units (12 centimorgans) apart

  • This corresponds to about 12 million base pairs of DNA

• This distance is:

  • Large enough for crossing over to occur

  • Small enough that the genes are still considered linked

Key takeaway:
Recombination frequency is a powerful tool for mapping gene location and distance along chromosomes.

Genes that are in close proximity to each other on the

same chromosome are inherited together. Examining

this pedigree on the inheritance and segregation of

the colour-blindness and haemophilia traits through a

family shows us that these two traits are linked. But

note the exception in the individual with only

hemophilia in generation IV. Linkage between the

gene for haemophilia and colour-blindness would

lead to the prediction that these two genes should be

inherited together, especially since that male’s

mother was a carrier for both. The fact that they are

not in these individuals is explained by the fact that

the separation of these alleles must have occurred by

crossing over or recombination of alleles. The

frequency of these types of exceptions can certainly

tell us something about the distance between genes.

The relative distance between genes on a

chromosome then allows researchers to create a

linkage map. A linkage map will show not only the

distance between chromosomes, but can also show

the order of genes along the chromosome. Looking

at this pedigree and considering the relative

frequency of recombinant individuals (in accordance

with many other pedigrees), it has been found that

the colour-blindness and haemophilia genes are

roughly 12 map units (or centimorgan) apart on the X

chromosome. This is about 12 million base pairs

apart. As a result, this distance is large enough for

crossing over to occur between these two gene

How do high‑density linkage maps using SNPs help identify human disease genes?

Linkage maps for human genes are useful, but as we

just saw, genes can lie millions of base pairs apart and

we need to be able to visualize a phenotype such as a

disorder in order to identify alternate alleles. This

makes these linkage maps impractical for human

applications.

Back

• Traditional linkage maps are impractical in humans because genes can be millions of base pairs apart and phenotypes are hard to visualize.

• High‑density linkage maps use SNPs and other non‑coding markers spaced only thousands of base pairs apart.

  • High-density linkage maps identify genetic loci that are merely a few thousand base pairs apart.

  • Having a map of SNPs in non-coding regions of the genome may not seem

useful, but these linkage maps can then be used to map human genes that determine various characteristics. The principle is the same as before. We are looking at the frequency of recombination to determine the relative distance between two genetic loci, whether they are genes, markers, or a gene and a marker

• Even though SNPs are non‑coding, they can be used to track nearby genes through recombination frequency.

• Recombination frequency shows distance:

  • High recombination (≈50%) → loci far apart → unlinked

  • Low recombination (<50%) → loci close together → linked

• Marker B (far from disease gene):

  • All four allele combinations occur 25% each

  • No association → unlinked

• Marker A (close to disease gene):

  • Mutant + G‑C and non‑mutant + A‑T occur ~49% each

  • Recombination is rare → linked

• Because SNP locations are known, linkage to markers reveals the approximate location of the disease gene.

Why are traditional linkage maps impractical for human gene mapping, and what is used instead?

Back:

• In humans, genes can be millions of base pairs apart, and phenotypes (like disorders) must be observed to identify alternate alleles.

• This makes traditional linkage maps impractical for human applications.

• Instead, scientists use high‑density linkage maps built from millions of SNPs and other non‑coding markers.

• These markers are only a few thousand base pairs apart, providing much finer resolution than gene‑only maps.

How do SNPs in non‑coding regions help map human genes?

Back:

• Although SNPs are in non‑coding regions, their positions in the genome are known.

• High‑density linkage maps use these SNPs to identify genetic loci located close together.

• The same principle as classic linkage mapping applies:

  • Scientists examine recombination frequency.

  • Lower recombination frequency means loci are closer together.

• These maps can locate genes responsible for human traits or diseases, even if the markers themselves have no function.

How does recombination frequency show whether a disease gene is linked to a genetic marker?

Back:

• The disease gene has two alleles: mutant and non‑mutant.

• The marker also has two alleles: G‑C or A‑T.

• Marker B (far from disease gene):

  • Recombination always occurs between them.

  • All four allele combinations appear 25% of the time.

  • There is no association → marker B and the disease gene are unlinked.

• Marker A (close to disease gene):

  • Recombination is rare.

  • Mutant + G‑C and non‑mutant + A‑T appear ~49% each.

  • Unequal frequencies show linkage.

• Because the marker’s genomic location is known, linkage reveals the approximate location of the disease gene.

How do high‑density SNP‑based linkage maps identify human disease genes using recombination frequency?

Back

Traditional linkage maps are impractical in humans because genes can be millions of base pairs apart, and identifying alleles requires visible phenotypes like disorders. Instead, scientists use high‑density linkage maps made from millions of SNPs and other non‑coding markers spaced only thousands of base pairs apart. High-density linkage maps identify genetic loci that are merely a few thousand base pairs apart. Although SNPs do not code for proteins, their genomic locations are known, allowing them to act as markers. Using the same principle as classic linkage mapping, recombination frequency is analyzed to estimate the distance between two loci (genes, markers, or a gene and a marker). A disease gene with mutant and non‑mutant alleles is compared to a marker with G‑C or A‑T alleles. When a marker (Marker B) is far from the gene, recombination always occurs, producing all four allele combinations equally (25%), indicating no association (unlinked). When a marker (Marker A) is close to the disease gene, recombination is rare, and parental allele combinations occur ~49% each, indicating linkage. Because marker positions are known, linkage reveals the approximate location of the disease gene.

How does recombination frequency show whether a disease gene is linked to a genetic marker (Marker A vs. Marker B)?

Back

• The disease gene has two alleles: mutant and non‑mutant.

• The marker also has two alleles: G‑C or A‑T.

Marker B (far from the disease gene):

• The gene and marker are so far apart that recombination always occurs.

• Marker alleles do not stay paired with specific gene alleles.

• All four allele combinations appear in offspring at equal frequency (25% each).

• This equal distribution shows no association → marker B and the disease gene are unlinked.

Marker A (close to the disease gene):

• The marker is near the disease gene, so recombination is rare.

• The mutant + G‑C and non‑mutant + A‑T combinations occur ~49% each.

• Unequal allele frequencies indicate an association → marker A and the disease gene are linked.

• Because marker locations are known from genome maps, linkage allows determination of the approximate location of the disease gene.

Above, the gene is represented by two alternate

alleles, a mutant and a non-mutant allele. The

marker is similarly represented by two alleles, a G-C

pair or an A-T pair. In image b, the gene is far away

from the marker, we will call this marker B. So far

away, that recombination will always occur in this

interval. As a result, the G-C marker allele does not

remain with the mutant allele and the A-T marker

allele does not remain with the G-C marker allele. We

see in the offspring, that the G-C allele is found with

the nonmutant alleles and that the A-T allele is found

with the mutant allele. Since we see all four of these

combinations of alleles with the same frequency, 25%

of the time each, we can say that there is no

association between the disease gene and marker B,

or they are unlinked. In contrast, in image a, we are

looking at a different marker, marker A. Here we see

that there is not an equal representation of the allele

combinations. The mutant allele with the G-C allele

and the nonmutant allele with the A-T allele occur

more frequently, 49% of the time each. This tells us

that recombination in between the disease gene and

marker A is rare and that the distance between these

two loci is relatively small. We can say that there is

an association between the disease gene and marker

A, of that they are linked. Since we know the exact

location of the markers from our human genome

maps, we now know the approximate location of the

disease gene

Why are Genome‑Wide Association Studies (GWAS) more powerful than pedigree analysis for mapping human genes?

Back:

• Pedigree analysis is limited to a few hundred or thousand related individuals, restricting statistical power and genetic diversity.

• With human SNP‑linkage maps and fast, inexpensive SNP genotyping, researchers can now analyze tens to hundreds of thousands of unrelated individuals.

• A Genome‑Wide Association Study (GWAS) examines SNPs across the entire genome to find associations between specific SNP alleles and phenotypes.

• Studying large, unrelated populations improves the ability to detect small genetic effects and increases mapping accuracy.

• GWAS allows researchers to identify the genomic locations of genes influencing traits without requiring family ancestry data

Pedigree analysis limits our studies to a few hundred

or perhaps a thousand individuals that are related

through ancestry. With the advent of human SNP-

linkage maps and the technology to quickly and

cheaply identify SNPs, researchers are able to look at

tens of thousands or hundreds of thousands of

unrelated individuals in a population in order to map

the location of genes.

How does GWAS identify genes that contribute to human traits, illustrated by the HMGA2 height example?

Back:

• GWAS detects statistical associations between a phenotype and specific SNP marker alleles.

• Example: An association between human height and SNPs near the HMGA2 gene revealed its role in height variation.

• HMGA2 has a small effect on height, contributing less than 1 cm of variation:

  • Individuals with two “C” alleles are 0.8 cm taller than individuals with two “T” alleles.

  • Heterozygous (C/T) individuals are 0.4 cm taller than individuals with two T alleles (intermediate effect).

• This shows that many human traits are influenced by genes with small additive effects.

• GWAS has been used to identify genes contributing to complex traits and diseases, including heart disease, cancer, and diabetes.

A Genome-Wide Association

Study (GWAS) looks across the entire SNP-linkage

map for an association between a particular

phenotype and a mapped SNP. For example, by

demonstrating an association between height and a

particular marker allele, researchers were able to

identify a gene that contributes to increased height in

humans. The gene, HMGA2 gene, contributes to less

than 1 cm variation in height. Individuals with two

“C” alleles of HMGA2 are 0.8cm taller than people

with two “T” alleles. Individuals heterozygous for the

“C” and “T” alleles are only 0.4cm taller than people

with the two “C” alleles. Such association studies

help researchers to identify genes that contribute to

various human characteristics including disease

phenotypes such as heart disease, cancer, and

diabetes