Evolution and Genetics: What are factors and theories of evolution that have affected the presentation of the VHL gene in modern mammals?

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Inherited germline genetic variant

Passed from parent to offspring

VHL is seen in all areas of the world, relatively equally in both sexes and all races

Second mutated allele

VHL may skip generations; Not all people get the second mutation

50% of cases have only one mutated allele

Undergoes somatic change resulting in loss of second allele

Generally unknown mutation triggers

Environmental

Physical factors

Chemical exposure

Chance errors in cell replication

Inheritance

Manifestation and Inheritance

Some with the mutation do not present with the disease

Some who present similar symptoms do not have the mutation

Subtopic

Chuvash (congenital) Polycythemia

Sexual Selection: Originally isolated within the Chuvash population of Russia

Caused by a high allele frequency of VHL in a reproductively isolated area

Has since presented worldwide

An autosomal recessive, inheritance of germline mutations in both VHL alleles

Missense homozygous mutation of 598C>T

C-terminal region, Elongin-C binding region, or close to it

May result from compound heterozygous genetic changes

P192A and L188V mutations in one allele, “polycythemia-causing” p.R200W in the second allele

Mutation

1600 different pathogenic variations and over 1800 entries for genetic variation in VHL gene collected on the VHL databases

Mutations in both copies of the VHL gene must appear for VHL to present

First allele mutation

De novo genetic change

Appears during the formation of gametes or in early stages of the zygote

Chromosome 3: Controls cell growth and cell death

Mutations in the nucleotides CC→ AA, in the range of 3p-21 to 3p-25

Caused by missense or deletion mutation

Caused by loss of function mutations; Deletions or Truncations

Most common genetic changes

Other gene fusions

Structural variations

Splice-site

Missense

Associated with worse prognoses/higher rates of fatal cysts and tumors

Point mutation

Truncating

Most destructive in the Sp 1 region

Insertions

Deletions

Frameshift

In-frame

In exons

Deletion and certain missense mutations result in an increased risk for hemangioblastoma and RCC formation

Evolution and Genetics: What are factors and theories of evolution that have affected the presentation of the VHL gene in modern mammals?

Von Hippel–Lindau: Genetic Disease affecting multiple organ systems

"Autosomal dominant cancer-predisposition due to inheritance of a single mutated allele of VHL"

Presentation in humans

Discovery

Named von Hippel Lindau in 1960

VHL gene was identified in 1993

Arvid Lindau

1923-1926: Got his PhD studying CNS tumor and cyst pathology

Eugen von Hippel

1911: Named the disease "angiomatosis retinae"

1904: First described rare disorder in the retina

Genotype-Phenotype correlation

However, each variation is associated with different increased probability of presenting certain tumors/cysts depending on depending which VHL type, which cell type, and the second mutation location

Type 2

Type 2C - No risk for renal cell carcinoma

Type 2B - High risk for renal cell carcinoma

Type 2A - Low risk for renal cell carcinoma

Type 1

Genetic Hallmarks

Cysts

Tumors

Non-Human Organisms

Dogs

90% similarity to humans

Renal cell carcinoma (RCC)

Dog oncogenesis differs

Lower prevalence of VHL mutations

Murinae Subfamily

Mice and Rats

Sequence conservation over 100 million years of evolution highlights evolutionarily conserved regions; When removed, testing showed a reduction in function of the VHL gene

Four evolutionarily conserved regions were identified; Nucleotide identity similarity above 65%

Region 2: Between nucleotides −49 to −19

Region 1: Between nucleotides +2 to +17

Primates

Olive Baboon

Entire VHL 5‘ sequence: 93% similarity

106 bp minimal promoter region: 95% similarity

Macaque

Diverged from primates earlier

Entire VHL 5‘ sequence: 45% similarity

106 bp minimal promoter region: 50% similarity

Gorillas

Entire VHL 5‘ sequence: 96% similarity

106 bp minimal promoter region: 97% similarity

Chimpanzees

Diverged from humans last

Entire VHL 5‘ sequence: 98% similarity

106 bp minimal promoter region: 99% similarity

Patterns of evolution

VHL, alongside factors HIF-1 and HIF-2, are involved in the hypoxia-sensing pathways, well-preserved among invertebrate and vertebrate species

HIFα has undergone multiple duplication events coinciding with the evolution of vertebrate species leading to great variation

"Variations in the VHL gene within different species is a result of divergent evolution, triggered by animals first diversifying between 600 and 500 million years ago under conditions that today would be described as hypoxic"

Combinations of VHL Phen+3 and HIF1α Metn-3 emerged during evolution through multiple lineages

Emerged approximately 500 million years ago in the modern-day lampreys' ancestors

Substitutions resulted in functional divergence

Specialized hypoxic signalling relative to vertebrate needs/oxygen consumption

VHL affinity to HIFa genes

HIFα-VHL complex stability varies between species and drives adaptation to their environments

Significant variation is tolerated due to unique selective pressures

Example: HIF1α Metn-3 is the most stable HIFα-VHL complex, present in many animals

Humans have three HIFα proteins

HIF3α

HIF2α

HIF1α

Most tightly bonded to VHL

Possess only one HIFα gene due to substitution of VHL Phe91 with Tyr genes

Example: HIFα Metn-3

Primary gene present in sequence analysis of metazoan oxygen-sensing species

Present in the last common ancestor to lophotrochozoa and ecdysozoa species

Diverged in the ecdysozoa

Larger evolutionary divergence due to lower VHL affinity

Duplication of ancestral hypoxia-inducible factor (HIF)α

Core proteins critical for oxygen-sensing)

Creation of (negative regulator) pVHL

Created the secondary contact between HIF1α Met561 and VHL Phe91 sequences

Both the presence and levels of similarly between the different species suggest that the VHL gene in a homologous feature