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

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

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

Duplication of ancestral hypoxia-inducible factor (HIF)α

Creation of (negative regulator) pVHL

Created the secondary contact between HIF1α Met561 and VHL Phe91 sequences

Core proteins critical for oxygen-sensing)

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

Larger evolutionary divergence due to lower VHL affinity

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

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

Humans have three HIFα proteins

HIF1α

Most tightly bonded to VHL

HIF2α

HIF3α

"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"

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

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

Significant variation is tolerated due to unique selective pressures

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

Primates

Chimpanzees

106 bp minimal promoter region: 99% similarity

Entire VHL 5‘ sequence: 98% similarity

Diverged from humans last

Gorillas

106 bp minimal promoter region: 97% similarity

Entire VHL 5‘ sequence: 96% similarity

Macaque

106 bp minimal promoter region: 50% similarity

Entire VHL 5‘ sequence: 45% similarity

Diverged from primates earlier

Olive Baboon

106 bp minimal promoter region: 95% similarity

Entire VHL 5‘ sequence: 93% similarity

Murinae Subfamily

Mice and Rats

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

Region 1: Between nucleotides +2 to +17

Region 2: Between nucleotides −49 to −19

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

Dogs

Renal cell carcinoma (RCC)

Lower prevalence of VHL mutations

Dog oncogenesis differs

90% similarity to humans

Genotype-Phenotype correlation

Type 1

Genetic Hallmarks

Tumors

Cysts

Type 2

Type 2A - Low risk for renal cell carcinoma

Type 2B - High risk for renal cell carcinoma

Type 2C - No risk for renal cell carcinoma

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

Discovery

Eugen von Hippel

1904: First described rare disorder in the retina

1911: Named the disease "angiomatosis retinae"

Arvid Lindau

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

Named von Hippel Lindau in 1960

VHL gene was identified in 1993

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

Most common genetic changes

Deletions

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

In exons

In-frame

Frameshift

Insertions

In-frame

Frameshift

Point mutation

Most destructive in the Sp 1 region

Truncating

Missense

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

Splice-site

Structural variations

Other gene fusions

Caused by loss of function mutations; Deletions or Truncations

Caused by missense or deletion mutation

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

Chromosome 3: Controls cell growth and cell death

First allele mutation

De novo genetic change

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

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

Missense homozygous mutation of 598C>T

May result from compound heterozygous genetic changes

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

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

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

Has since presented worldwide

Manifestation and Inheritance

Some who present similar symptoms do not have the mutation

Some with the mutation do not present with the disease

Inherited germline genetic variant

Second mutated allele

Undergoes somatic change resulting in loss of second allele

Generally unknown mutation triggers

Chance errors in cell replication

Environmental

Chemical exposure

Physical factors

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

50% of cases have only one mutated allele

Passed from parent to offspring

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