Oxford Hair Foundation Genetics of Scalp Disorders

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Oxford Hair FoundationGenetics of Scalp
Disorders

• Thomas L. Dawson, Jr., Ph.D.

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What is Dandruff?
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Dandruff Physiology
Dandruff flakes are the opposite of dry skin
Leg skin, 21,600X
Dandruff, 27,000X
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Dandruff Physiology
Dandruff scalp
Non-Dandruff
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Dandruff Physiology
Non-Dandruff
Dandruff scalp
75K mag.
94 K mag.
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What is dandruff summary

• Dandruff is a less severe form of seborrheic
  dermatitis
• Dandruff is the opposite of dry skin
• excess lipids
• no desmosomes

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Dandruff Microbiology

• Current hypotheses implicate microorganisms
  infecting the scalp, predominantly Malassezia
  fungi
• Malassezia fungus is found on all scalps, but
• Malassezia actually consists of at least ten
  species,

M. furfur M. pachydermatis M. sympodialis M.
globosa M. obtusa
M. slooffiae M. restricta M. dermatis M. japonica
M. equi
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So then, Who is really there?
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Genomics I - Application of Genetic Tools to
Dandruff Aetiology

• M. furfur or P. ovale is frequently cited as the
  dandruff causal organism, based on culture
  methods
• Genomics-based techniques identify the actual
  culprits, M. restricta and M. globosa

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Why Genomic Speciation?
No bias on culture!
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Malassezia Species on Human Scalp
ASFS lt10 (N24)
ASFS gt24 (N46)
Frequency ( of N)
No fungi detected
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So, whos the culprit?
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Mechanism
How do Malassezia restricta and globosa cause
dandruff?
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Hyper-Proliferation Caused by Inflammation
Sebaceous
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• Oleic acid, alone, can induce dandruff in human
  subjects

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Flaking
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Days Treatment
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Which Malassezia Species Causes Dandruff?
Malassezia globosa is mostly likely the causative
agent based on prevalence activity
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Genomics II - Cloning of the M. globosa Lipase
H2N-GRGGSST DQPVANPYNT KEISLAAGLV QQTYCDSTEN
GLKIGDSELL YTMGEGYARQ RVNIYHSPSL
GIAVAIEGTN LFSLNSDLHD AKFWQEDPNE RYIQYYPKGT
KLMHGFQQAY NDLMDDIFTA VKKYKKEKNE
KRVTVIGHSL GAAMGLLCAM DIELRMDGGL
YKTYLFGLPR LGNPTFASFV DQKIGDKFHS IINGRDWVPT
VPPRALGYQH PSDYVWIYPG NSTSAKLYPG
QENVHGILTV AR
Yellow peptide sequence Red - conserved
active site Pink peptide sequence
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Genomics III - The Future
Comparative Whole-genome Analysis
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Some sequenced fungal genomes
Saccharomyces cerevisiae the quintessential
fungus
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Some sequenced fungal genomes
Ustilago maydis - Malassezias near neighbour
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Some sequenced fungal genomes

• Candida albicansa - common human pathogen

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Some sequenced fungal genomes

• Cryptococcus neoformans - another common human
  pathogen

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The Whitehead Initiative!
7 Fungal Genomes Sequenced 44 genomes proposed
to be sequenced
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The problem

• Fungal infections and fungal-related mortality is
  on the rise
• Current anti-fungal therapies essentially rely on
  four gene targets

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Progress from functional genomics

• Genomics research has defined new families of
  essential genes
• Genomics research has developed new models to
  much more rapidly assess the effects of
  disruption of these essential targets

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Progress from functional genomics

• Now, we have gone from four known targets to
  hundreds of targets in thousands of genes
• The trick now becomes what are the best of
  these targets, and how do we find new materials?

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Progress from functional genomics

• New target identification
• Is the proposed target present in the genome?
• Is the target relevant to the disease/disorder?
• Is the target testable in a validated assay?
• Is it expressed in situ?

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On the horizon

• Fusion of human and fungal genome data, to
  decipher the communication between host and
  fungus
• Replace anti-fungal technology with
  normalization technology!

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The Team

• PG
• Joe Kaczvinsky
• Charlie Saunders
• Tina Gemmer
• Yvonne DeAngelis
• Erin MacDonald
• Meredith Leland
• Kevin Johnstone
• Mariann Jenkins

• Collaborators
• Aditya Gupta, MD, PhD, MediProbe Labs, Canada
• Teun Boekhout, PhD, The CBS, The Netherlands
• Jim Kronstad, PhD, Univ. British Columbia
• George Smulian, Univ. Cincinnati, USA
• Bo Yuan, Ohio State, USA
• Pamela Troller, Augustana College, USA

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Thank You