Ying-Hui Fu () is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for
circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
disorders, and characterizing genetic forms of
demyelinating degenerative disorders. Fu is currently a professor of neurology at the
University of California, San Francisco
The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California. It is part of the University of California system and is dedicated entirely to health science and life science. It cond ...
. She was elected to the US
National Academy of Sciences
The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the Nati ...
in 2018.
Background and education
Early career
In 1980, Fu received a degree in food science from
National Chung-Hsing University in Taiwan. In her study of food sciences, she was introduced to biochemistry and microbiology, which led her to study DNA manipulation. She then received her Ph.D. in biochemistry and molecular biology from
Ohio State University
The Ohio State University, commonly called Ohio State or OSU, is a public land-grant research university in Columbus, Ohio. A member of the University System of Ohio, it has been ranked by major institutional rankings among the best publ ...
in 1986. She continued to work at OSU for three more years in a post-doctoral position studying gene regulation in fungi. During her time at OSU, she cloned numerous genes important for nitrogen and sulfur metabolism in ''Neurospora''. One of these genes, cys-3, encodes a leucine zipper protein. It was hypothesized that leucine zippers were DNA-binding elements. The first proof of this in living organisms was a mutation in the cys-3 leucine zipper, which caused a sulfur metabolism defect. After studying the mutation, Fu demonstrated that the mutated cys-3 was unable to bind DNA.
In 1989, Fu transferred to the
Baylor College of Medicine
Baylor College of Medicine (BCM) is a medical school and research center in Houston, Texas, within the Texas Medical Center, the world's largest medical center. BCM is composed of four academic components: the School of Medicine, the Graduate Sc ...
as a post-doctoral fellow to study human genetics.
While there, she was part of the team that identified the
fragile-X syndrome gene. The gene contains a polymorphic CGG trinucleotide repeat in their DNA sequence; the repeat ranged from 6 to 54 in individuals with normal X chromosomes. The transition from stable to unstable occurred between 46 and 52 repeats. The instability increases the likelihood of fragile-X mental retardation. The repeats have a tendency to expand in transmission through meiosis. The size of the repeat correlates with severity of the disease. Fu cloned one of the genes responsible for a form of muscular dystrophy called
myotonic dystrophy
Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intel ...
, and showed that an expanded trinucleotide repeat in this gene also was unstable and caused the disease. Together, these discoveries characterized the molecular basis of genetic “anticipation,” the phenomenon of worsening severity in subsequent generations, as being due to unstable, expanded trinucleotide repeats.
Biomedical industry
After her postdoc position, Fu worked in biotech industry for four years before returning to academia. She worked first for two years from January 1993 - 1995 at
Millennium Pharmaceutical Corporation, a biopharmaceutical company focused on oncology and inflammation (later acquired by
Takeda Pharmaceutical Company
The is a Japanese multinational pharmaceutical company, with partial American and British roots. It is the largest pharmaceutical company in Asia and one of the top 20 largest pharmaceutical companies in the world by revenue (top 10 followin ...
). After leaving Millennium Pharmaceutical, from 1995- August 1997 Fu worked for Darwin Molecular Corporation for two years and took part in the search for mutations responsible for premature aging (
Werner syndrome
Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare, autosomal recessive disorder ...
) and early onset
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(
presenilin 2).
Recent career
In 1997, Fu returned to academia, taking the position of associate professor of research at the
University of Utah
The University of Utah (U of U, UofU, or simply The U) is a public research university in Salt Lake City, Utah. It is the flagship institution of the Utah System of Higher Education. The university was established in 1850 as the University of De ...
. Fu was then recruited to the University of California, San Francisco in 2002, where she is a co-principal investigator (PI) with her collaborator, Louis Ptacek.
The lab's current projects include: locating human sleep genes, uncovering the molecular mechanisms of human sleep regulation and human circadian rhythms, investigating mouse models with de/dys-myelinating disease, and classifying miRNAs that contribute to healthy myelin.
Research interests
Human sleep behaviors
Circadian rhythms and metabolism
Fu had her training in molecular biology and human genetics, but she became interested in circadian rhythms in 1996 when a woman came into a sleep clinic at the University of Utah, complaining that she had to go to bed very early and would wake up very early. This woman and her family would become the subject of study for Fu and her collaborator Louis Ptacek for
familial advanced sleep phase syndrome (FASPS). They cloned the causative gene/mutation and studied the ''in vitro'' biochemical consequences of the mutation, culminating in a 2001 paper An h''Per2'' phosphorylation site mutation in familial advanced sleep-phase syndrome, reporting the first circadian gene mutation in humans.
Familial advanced sleep phase syndrome
In 2001, Fu and her collaborator's labs published a paper that explained a phenotype of extremely early risers in humans called Familial Advanced Sleep Phase Syndrome (FASPS). Humans with this
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
disease typically go to bed around 7:00 p.m. and wake up at 3:00 a.m. The lab studied the genomes of people with this trait and found a point mutation in the
PER2
PER2 is a protein in mammals encoded by the ''PER2'' gene. ''PER2'' is noted for its major role in circadian rhythms.
Discovery
The ''per ''gene'' ''was first discovered using forward genetics in ''Drosophila melanogaster, Drosophilla melanoga ...
gene that likely causes the behavioral phenotype.
Short sleep phenotype
In 2009, Fu's group published a paper that explained the mechanisms of a short sleep phenotype in humans. In one family, carriers of the
autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
phenotype sleep 6.25 hours compared to non-carrying family members, who sleep more than 8 hours per night. Fu traced the phenotype back to a point mutation in a gene called
DEC2
"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previ ...
that is associated with short sleep phenotype in humans. The mutant DEC2 has a
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
-to-
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
switch at amino acid position 384, which causes the short sleep phenotype.
Transgenic
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
mice and flies with the mutant DEC2 showed similar phenotypes. It is not currently known what other molecules DEC2 interacts with to produce the short sleep phenotype.
Neurodegeneration
Trinucleotide repeat expansions and neurological diseases
When Fu did her post-doctoral work in Baylor College, she was part of the team that was positional cloning the Fragile-X syndrome gene. There, she studied the trinucleotide repeat sequence expansions, the mutations responsible for the Fragile-X Syndrome, and their correlation with disease severity and age of onset. This work led to the discovery of underlying molecular mechanism for genetic anticipation. Following this work, she cloned the gene responsible for Myotonic dystrophy based on the hypothesis that genetic anticipation in Myotonic dystrophy is also caused by trinucleotide repeat expansion on patient DNA. This mutational mechanism is now known to cause not only Fragile X syndrome and Myotonic dystrophy, but also Huntington's disease and many of the spinocerebellar ataxias. Thus, it is a common mutational mechanism in inherited neurological diseases.
Autosomal Dominant Leukodystrophy (ADLD)
In 2006, Fu's lab published a paper characterizing a mutation that led to ADLD in humans. Adult-onset autosomal dominant leukodystrophy (ADLD) is a neurological disorder that is associated with widespread myelin loss in the central nervous system. Fu's lab traced the phenotype back to individuals with an extra copy of nuclear laminar protein
lamin B1
Lamin-B1 is a protein that in humans is encoded by the ''LMNB1'' gene.
The nuclear lamina consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly ...
making ADLD one of the diseases named “laminopathies”.
Awards
* Sleep Science Award from the American Academy of Neurology (2006)
* Bauer Foundation Colloquium Distinguished Guest, Brandeis University, Boston, MA (2006)
* Distinguished Guest, Bollum Symposium, University of Minnesota, Minneapolis, MN (2008)
* Distinguished visiting professorship, Tamkang University, Taiwan (2009)
* Faculty Research Lecture in Basic Research, UCSF (2012)
* Presidential Lecture, University of Vermont (2012)
* Elected Member,
National Academy of Sciences
The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the Nati ...
(2018)
* Elected member,
National Academy of Medicine
The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, En ...
, 2018
Selected publications
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See also
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Neuroscience of sleep
The neuroscience of sleep is the study of the neuroscience, neuroscientific and Physiology, physiological basis of the nature of sleep and its functions. Traditionally, sleep has been studied as part of psychology and medicine. The study of sleep ...
References
External links
Official profile at University of California* Official lab profile in collaboration with Louis Ptacek's lab a
Fu's personal website
{{DEFAULTSORT:Fu, Ying-Hui
American women biologists
Year of birth missing (living people)
Living people
National Chung Hsing University alumni
Ohio State University alumni
Taiwanese emigrants to the United States
University of California, San Francisco faculty
Members of the United States National Academy of Sciences
Taiwanese biologists
Taiwanese women scientists
21st-century American women