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					8                     inheriTeD DiseAses

                                              “our ultimate goal is to create better
                                      medicine that can heal patients or, optimally,
                                      that we can understand diseases so well that
                                              we can avoid them developing at all”
                                                                              kasper lage, postdoctoral fellow, harvard medical school and
                                                                                                        Broad institute of miT and harvard

                     of inheriTeD DiseAses
                      dTu collaboration with researchers from harvard medical school has mapped
                      and published links between genes, protein complexes and tissue types for more
                      than 1000 inherited diseases

                      Diseases and disorders such as          valuable material for medical re-         (brain cells differing in function from
                      Parkinson’s disease, heart disease,     searchers.                                muscle cells), different genes are active
                      breast cancer and autism may be in-                                               in various types of cells depending
                      herited because gene mutations can      millions of data on the web               on which proteins each cell needs.
                      be passed on to the next generation.    The two researchers started with the      By integrating the data from the two
                      Although all cells in a person’s body   many Internet data resources. The         databases, the researchers found out
                      contain precisely the same genetic             ®
                                                              OMIM (Online Mendelian Inherit-           which known disease-linked genes
                      code, including the mutated genes,      ance in Man) database includes more       are active in which types of tissue in
                      each disease develops solely in very    than 1000 inherited diseases and some     healthy humans.
                      specific areas or tissue. Niclas Tue    genes that cause them. Another da-           The next step was to investigate
                      Hansen and Kasper Lage, PhD fel-        tabase has measurements of the gene       which types of tissue inherited dis-
                      lows at the DTU Department of           expression in healthy tissue. A gene is   eases affect. They did this by advanced
                      Systems Biology, decided to find out    expressed when the protein for which      text analysis of more than 13 million
                      why. The result is an online atlas of   the gene encodes is created. Since hu-    scientific articles on inherited dis-
                      inherited diseases that is providing    man cells have very diverse functions     eases. The results showed that the          >>

TechnicAl UniversiT y of DenmArk

                                                                                         This figure shows the most important results of two con-
                                                                                         ditions investigated: dosage-sensitive sex reversal and
                                                                                         Parkinson’s disease. Parkinson’s disease creates a protein–
                                                                                         gene complex comprising five proteins and encoded genes.
                                                                                         Three are involved in Parkinson’s disease (colored red in the
                                                                                         box below). one hypothesis could therefore be that the last
                                                                                         two proteins in the complex are also involved in developing
                                                                                         Parkinson’s disease but that this has not yet been discov-
                                                                                         ered. This could be investigated.
                                                                                             another approach is to examine in which tissue the pro-
                                                                                         tein complexes exist. for example, the protein complex in
                                                                                         Parkinson’s disease is present in three types of tissue. The
                                                                                         first two are known targets for the disease. The last type
                                                                                         has not previously been associated with Parkinson’s disease.
                                                                                         could there be a connection?

                                                                                           condition: Parkinson’s disease
                                                                                           expression in tissue types:
                                                                                                                                     sncAip       Th
                                                                                           caudate nucleus: 0.668
                                                                                           subthalamic nucleus: 0.251
                                                                                           Globus pallidus: 0.119                              sncA
                                                                                           cell part:                            lAmp2
                                                                                           Presynaptic membrane
                                                                                           biological process:                                psmc3
                                                                                           catecholamine metabolism

                                                                                           condition: dosage-sensitive sex reversal
i l l U s T r AT i o n : s h u T T e r s T o c k / s e B a s T i a n k a u l i T z k i

                                                                                           expression in tissue types:
                                                                                           Testis: 0.432
                                                                                           interstitial cells of leydig         soX8             nfyA
                                                                                           (testis): 0.338
                                                                                           ovaries: –0.678                              nr5A1
                                                                                                                            nrob1                     pnrc2
                                                                                           cell part:
                                                                                           biological process:                       nrob2
                                                                                                                              esr1             soX9
                                                                                           regulation of transcription

                                                                                                                                                         DTU 2009
10                    inheriTeD DiseAses

                                        interstitial cells of leydig (testis)

                                                                                                                                                                                                                                                                                                                                                  subthalamic nucleus

                                                                                                                                                                                                                                                                                                                                                                                                  cardiac myocytes
                                                                                                                                                                                                                                                                                                                                                                        caudate nucleus

                                                                                                                                                                                                                                                                                                                                                                                                                     skeletal muscle
                                                                                                                                                                                                                                                                                                   spinal ganglion
                                                                                         smooth muscle

                                                                                                                                                                                                                                                                                                                                globus pallidus
                                                                                                                         Pituitary gland

                                                                                                                                                                                                                                                     Temporal lobe
                                                                                                                                           adrenal gland

                                                                                                                                                                                                     Bone marrow

                                                                                                                                                                                                                                                                     Parietal lobe
                                                                                                                                                                                lymph node


                                                                                                                                                                                                                                                                                     spinal cord



                                                                                                                                                                                                                   B cells



                                                                                                                                                                                                                                                                                                                                                                                                                                       alcohol-responsive myoclonic dystonia
                                                                                                                                                                                                                                                                                                                                                                                                                                       Parkinson’s disease
                                                                                                                                                                                                                                                                                                                                                                                                                                       dosage-sensitive sex reversal
                                                                                                                                                                                                                                                                                                                                                                                                                                       hereditary motor and sensory polyneuropathy (type iii)
                                                                                                                                                                                                                                                                                                                                                                                                                                       erb’s muscular dystrophy
                                                                                                                                                                                                                                                                                                                                                                                                                                       chronic lymphoid leukemia
                                                                                                                                                                                                                                                                                                                                                                                                                                       fanconi anemia
                                                                                                                                                                                                                                                                                                                                                                                                                                       medullary blastoma
                                                                                                                                                                                                                                                                                                                                                                                                                                       Turcot’s syndrome
                                                                                                                                                                                                                                                                                                                                                                                                                                       uterus and breast cancer
                                                                                                                                                                                                                                                                                                                                                                                                                                       von-hippel-lindau’s syndrome
                                                                                                                                                                                                                                                                                                                                                                                                                                       Benign metastatic leiomyoma
                                                                                                                                                                                                                                                                                                                                                                                                                                       epidermolysis bullosa simplex

                      researchers have used computers to analyze the abstracts of 13 million articles to find links between diseases and disorders and types of
                      tissue. This has enabled them to create a matrix describing which types of tissue are affected when people develop hundreds of inherited
                      diseases and disorders. This figure shows a small part of this matrix. The darker the color, the stronger the link.

                      types of tissue affected by a specific in-                                                                                                                                                             compiled unique material that linked                                                                                                                                                                        biological sex characteristics. Niclas
                      herited disease are those in which the                                                                                                                                                                 more than 1000 inherited diseases and                                                                                                                                                                       and Kasper’s results for this inherited
                      mutated genes are overexpressed.                                                                                                                                                                       numerous inherited types of cancer                                                                                                                                                                          condition produced by extensive map-
                                                                                                                                                                                                                             with more than 1200 known disease-                                                                                                                                                                          ping were identical to the clinical data
                      proteins linked to diseases                                                                                                                                                                            linked genes, 70 specific types of tissue                                                                                                                                                                   Patricia K. Donahoe had from people
                      The researchers took the project a                                                                                                                                                                     and more than 1500 protein complexes.                                                                                                                                                                       with dosage-sensitive sex reversal. The
                      step further to include the proteins                                                                                                                                                                                                                                                                                                                                                                               results documented some of the as-
                      involved in the diseases. In many in-                                                                                                                                                                  harvard researchers confirm                                                                                                                                                                                 sumptions about the causes of dosage-
                      herited diseases, mutations in different                                                                                                                                                               the results                                                                                                                                                                                                 sensitive sex reversal. Further, the
                      genes can lead to the same disease. The                                                                                                                                                                Kasper Lage traveled to Harvard                                                                                                                                                                             results indicated new connections that
                      reason is that the proteins for which                                                                                                                                                                  Medical School to discuss the method                                                                                                                                                                        had not been tested, and these could
                      the genes encode and that control all                                                                                                                                                                  and the utility of the results with some                                                                                                                                                                    be tested clinically.
                      bodily processes appear in functional                                                                                                                                                                  leading medical researchers. Patricia                                                                                                                                                                          Another Harvard research group
                      groups called protein complexes in                                                                                                                                                                     K. Donahoe, Professor and Director,                                                                                                                                                                         focusing on Parkinson’s disease
                      which proteins interact. If one protein                                                                                                                                                                Pediatric Surgical Research Laborato-                                                                                                                                                                       saw the results for this disease, with
                      loses its function, the whole complex                                                                                                                                                                  ries, Massachusetts General Hospital,                                                                                                                                                                       similar accordance. This initiated
                      often loses its function and disease may                                                                                                                                                               conducts research on dosage-sensitive                                                                                                                                                                       extensive collaboration in which
                      arise. Since the model included data on                                                                                                                                                                sex reversal, which leads to a differ-                                                                                                                                                                      Harvard Medical School researchers
                      protein interactions, the researchers                                                                                                                                                                  ence between chromosomal sex and                                                                                                                                                                            participated in testing, validating and

TechnicAl UniversiT y of DenmArk

Proteins that interact physically tend to be involved in the same functions.
mutations in genes that code for these proteins therefore often lead to the same
diseases. By studying the patterns in protein–protein interaction networks (as
shown here), researchers can find new disease genes. This enables better under-
standing of the diseases and can lead to the development of new drugs.

developing a Web atlas (available via                  The presentation of the project’s        analyzed. The researchers cannot yet
www.cbs.dtu.dk/diseaseatlas).                       results is the first step on the way to     explain why, but cancer, even inherit-
   Kasper Lage is now employed as                   better understanding the development        able cancer, seems to differ fundamen-
a postdoctoral fellow at Harvard                    of inherited diseases. The new atlas        tally from all other diseases. This can
Medical School. Patricia K. Donahoe                 provides thousands of surprises and         be an important clue for the cancer
describes the collaboration with the                clues that medical experts and genetic      researchers in their continuing study
DTU researchers:                                    researchers can follow up within their      of what cancer is and how to treat it. <
   “Combining our knowledge on                      specific fields.
the diseases with the newest research                                                                                    iben JUlie schmiDT

by leading systems biologists at the                new knowledge on cancer
DTU Center for Biological Sequence                  The researchers’ analysis has already
Analysis has led to a unique method                 provided two important results. They            inTomics
of analyzing inheritable diseases.                  showed that tissue affected by a dis-           The methods developed in the research
Our results have great potential in                 ease overexpresses the disease-related          project have led to the dTu spin-off company
understanding the processes involved                genes. This applies across the 1000             intomics. it offers the pharmaceutical industry
in hundreds of inherited diseases.                  diseases analyzed despite their vast            advanced data integration of the company’s
We hope that this can create better                 differences and thus seems to be gener-         own data with all existing data in the field.
treatment strategies for many serious               alizable. Nevertheless, this does not ap-       see www.intomics.com.
diseases.”                                          ply to the 59 inheritable types of cancer

                                                                                                                                                      DTU 2009

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