{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:04:06Z","timestamp":1790805846423,"version":"4.1.0"},"posted":{"date-parts":[[2024,9,15]]},"group-title":"Bioinformatics","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,15]],"date-time":"2024-09-15T00:00:00Z","timestamp":1726358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences lead to amyloid deposition could facilitate faster diagnosis and lead to new treatments.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Light chain sequences are collected in the Boston University AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    AL-Base now contains 2,193 monoclonal light chain sequences from plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes,\n                    <jats:italic>IGKV1-16<\/jats:italic>\n                    and\n                    <jats:italic>IGLV1-36<\/jats:italic>\n                    , were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated \u03ba light chains harbored significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated \u03bb light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.11.612490","type":"posted-content","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T01:39:53Z","timestamp":1726450793000},"source":"Crossref","is-referenced-by-count":3,"title":["An updated AL-Base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1275-2010","authenticated-orcid":false,"given":"Gareth","family":"Morgan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison N.","family":"Nau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Spencer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axin","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Bullard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishali","family":"Sanchorawala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Prokaeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024091904052751000_2024.09.11.612490v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2304088"},{"key":"2024091904052751000_2024.09.11.612490v1.2","doi-asserted-by":"crossref","first-page":"1203425","DOI":"10.3389\/fimmu.2023.1203425","article-title":"Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe","volume":"14","year":"2023","journal-title":"Front Immunol"},{"key":"2024091904052751000_2024.09.11.612490v1.3","doi-asserted-by":"crossref","first-page":"10664","DOI":"10.1039\/C8CC04396E","article-title":"Immunoglobulin light chain amyloid aggregation","volume":"54","year":"2018","journal-title":"Chem Commun"},{"key":"2024091904052751000_2024.09.11.612490v1.4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3109\/10428199709059685","article-title":"Incidence and impact of light chain associated (AL) amyloidosis on the prognosis of patients with multiple myeloma treated with autologous transplantation","volume":"27","year":"1997","journal-title":"Leuk Lymphoma"},{"key":"2024091904052751000_2024.09.11.612490v1.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-008-0554-0"},{"key":"2024091904052751000_2024.09.11.612490v1.6","doi-asserted-by":"publisher","DOI":"10.1080\/13506120802676781"},{"key":"2024091904052751000_2024.09.11.612490v1.7","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1038\/s41467-024-49520-6","article-title":"Light chain mutations contribute to defining the fibril morphology in systemic AL amyloidosis","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2024091904052751000_2024.09.11.612490v1.8","doi-asserted-by":"crossref","first-page":"319","DOI":"10.3390\/biomedicines8090319","article-title":"Immunoglobulins or Antibodies: IMGT\u00ae Bridging Genes, Structures and Functions","volume":"8","year":"2020","journal-title":"Biomedicines"},{"key":"2024091904052751000_2024.09.11.612490v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23880-9"},{"key":"2024091904052751000_2024.09.11.612490v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-93019-9"},{"key":"2024091904052751000_2024.09.11.612490v1.11","first-page":"147","article-title":"AB-Amy: machine learning aided amyloidogenic risk prediction of therapeutic antibody light chains","volume":"6","year":"2023","journal-title":"Antib Ther"},{"key":"2024091904052751000_2024.09.11.612490v1.12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-743997"},{"key":"2024091904052751000_2024.09.11.612490v1.13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-01-0114"},{"key":"2024091904052751000_2024.09.11.612490v1.14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-355784"},{"key":"2024091904052751000_2024.09.11.612490v1.15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-09-2707"},{"key":"2024091904052751000_2024.09.11.612490v1.16","doi-asserted-by":"publisher","DOI":"10.1002\/art.22959"},{"key":"2024091904052751000_2024.09.11.612490v1.17","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1996.0297"},{"key":"2024091904052751000_2024.09.11.612490v1.18","doi-asserted-by":"crossref","first-page":"e8771","DOI":"10.7717\/peerj.8771","article-title":"Biochemical and biophysical characterisation of immunoglobulin free light chains derived from an initially unbiased population of patients with light chain disease","volume":"8","year":"2020","journal-title":"PeerJ"},{"key":"2024091904052751000_2024.09.11.612490v1.19","first-page":"E389","article-title":"Single-molecule real-time sequencing of the M protein: Toward personalized medicine in monoclonal gammopathies","volume":"97","year":"2022","journal-title":"Am J Hematol"},{"key":"2024091904052751000_2024.09.11.612490v1.20","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.kint.2021.10.017","article-title":"RNA-based immunoglobulin repertoire sequencing is a new tool for the management of monoclonal gammopathy of renal (kidney) significance","volume":"101","year":"2022","journal-title":"Kidney Int"},{"key":"2024091904052751000_2024.09.11.612490v1.21","doi-asserted-by":"crossref","first-page":"1167235","DOI":"10.3389\/fimmu.2023.1167235","article-title":"Complete variable domain sequences of monoclonal antibody light chains identified from untargeted RNA sequencing data","volume":"14","year":"2023","journal-title":"Front Immunol"},{"key":"2024091904052751000_2024.09.11.612490v1.22","doi-asserted-by":"crossref","first-page":"e112","DOI":"10.1038\/bcj.2013.12","article-title":"Molecular analysis of immunoglobulin genes reveals frequent clonal relatedness in double monoclonal gammopathies","volume":"3","year":"2013","journal-title":"Blood Cancer J"},{"key":"2024091904052751000_2024.09.11.612490v1.23","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2023-0591"},{"key":"2024091904052751000_2024.09.11.612490v1.24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/13506129.2022.2095618","article-title":"Identification of AL proteins from 10 \u03bb-AL amyloidosis patients by mass spectrometry extracted from abdominal fat and heart tissue","volume":"30","year":"2023","journal-title":"Amyloid"},{"key":"2024091904052751000_2024.09.11.612490v1.25","first-page":"453","article-title":"Bence Jones proteins and light chains of immunoglobulins","volume":"70","year":"1982","journal-title":"Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda). J Clin Invest"},{"key":"2024091904052751000_2024.09.11.612490v1.26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800708"},{"key":"2024091904052751000_2024.09.11.612490v1.27","doi-asserted-by":"publisher","DOI":"10.1002\/PRO.4205"},{"key":"2024091904052751000_2024.09.11.612490v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.17.3389"},{"key":"2024091904052751000_2024.09.11.612490v1.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0111726"},{"key":"2024091904052751000_2024.09.11.612490v1.30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601850"},{"key":"2024091904052751000_2024.09.11.612490v1.31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00537"},{"key":"2024091904052751000_2024.09.11.612490v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0934-8"},{"key":"2024091904052751000_2024.09.11.612490v1.33","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1038\/s41467-019-09481-7","article-title":"Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage","volume":"10","year":"2019","journal-title":"Nat Commun"},{"key":"2024091904052751000_2024.09.11.612490v1.34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601415"},{"key":"2024091904052751000_2024.09.11.612490v1.35","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8648-4_3"},{"key":"2024091904052751000_2024.09.11.612490v1.36","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-842-9_32"},{"key":"2024091904052751000_2024.09.11.612490v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp946"},{"key":"2024091904052751000_2024.09.11.612490v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt382"},{"key":"2024091904052751000_2024.09.11.612490v1.39","doi-asserted-by":"publisher","DOI":"10.1159\/000049195"},{"key":"2024091904052751000_2024.09.11.612490v1.40","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria; 2022. Available from: https:\/\/www.R-project.org\/."},{"key":"2024091904052751000_2024.09.11.612490v1.41","first-page":"4","volume":"7","year":"2015","journal-title":"Peptides: A Package for Data Mining of Antimicrobial Peptides. R J"},{"key":"2024091904052751000_2024.09.11.612490v1.42","unstructured":"RStudio Team. RStudio: Integrated Development Environment for R [Internet]. Boston, MA: RStudio, PBC.; 2020. Available from: http:\/\/www.rstudio.com\/."},{"key":"2024091904052751000_2024.09.11.612490v1.43","unstructured":"Pag\u00e8s H , Aboyoun P , Gentleman R , et al. Biostrings: Efficient manipulation of biological strings [Internet]. 2022. Available from: https:\/\/bioconductor.org\/packages\/Biostrings."},{"key":"2024091904052751000_2024.09.11.612490v1.44","unstructured":"Robinson D , Hayes A , Couch S. broom: Convert Statistical Objects into Tidy Tibbles [Internet]. 2023. Available from: https:\/\/CRAN.R-project.org\/package=broom."},{"key":"2024091904052751000_2024.09.11.612490v1.45","unstructured":"Kassambara A. ggpubr: \u2018ggplot2\u2019 Based Publication Ready Plots [Internet]. 2023. Available from: https:\/\/CRAN.R-project.org\/package=ggpubr."},{"key":"2024091904052751000_2024.09.11.612490v1.46","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv494"},{"key":"2024091904052751000_2024.09.11.612490v1.47","unstructured":"Kassambara A. rstatix: Pipe-Friendly Framework for Basic Statistical Tests [Internet]. 2023. Available from: https:\/\/CRAN.R-project.org\/package=rstatix."},{"key":"2024091904052751000_2024.09.11.612490v1.48","unstructured":"Perepolkin D. polite: Be Nice on the Web [Internet]. 2023. Available from: https:\/\/CRAN.R-project.org\/ package=polite."},{"key":"2024091904052751000_2024.09.11.612490v1.49","doi-asserted-by":"crossref","first-page":"520","DOI":"10.32614\/RJ-2017-058","article-title":"rentrez: An R package for the NCBI eUtils API","volume":"9","year":"2017","journal-title":"R J"},{"key":"2024091904052751000_2024.09.11.612490v1.50","unstructured":"Wickham H. rvest: Easily Harvest (Scrape) Web Pages [Internet]. 2022. Available from: https:\/\/CRAN.R-project.org\/package=rvest."},{"key":"2024091904052751000_2024.09.11.612490v1.51","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the tidyverse","volume":"4","year":"2019","journal-title":"Journal of Open Source Software"},{"key":"2024091904052751000_2024.09.11.612490v1.52","doi-asserted-by":"crossref","unstructured":"Gasteiger E , Elisabeth G , Christine H , et al. Protein Identification and Analysis Tools on the ExPASy Server. The Proteomics Protocols Handbook. 2005. p. 571\u2013607.","DOI":"10.1385\/1-59259-890-0:571"},{"key":"2024091904052751000_2024.09.11.612490v1.53","doi-asserted-by":"crossref","unstructured":"Schreiner S , Berghaus N , Poos AM , et al. Sequence diversity of kappa light chains from patients with AL amyloidosis and multiple myeloma. Amyloid. 2024;1\u20139.","DOI":"10.1080\/13506129.2023.2295221"},{"key":"2024091904052751000_2024.09.11.612490v1.54","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16805"},{"key":"2024091904052751000_2024.09.11.612490v1.55","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709974"},{"key":"2024091904052751000_2024.09.11.612490v1.56","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.50.0892"},{"key":"2024091904052751000_2024.09.11.612490v1.57","doi-asserted-by":"crossref","first-page":"8010","DOI":"10.1200\/JCO.2019.37.15_suppl.8010","article-title":"Seeking light-chain amyloidosis very early: The SAVE trial\u2014 identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma","volume":"37","year":"2019","journal-title":"JCO"},{"key":"2024091904052751000_2024.09.11.612490v1.58","doi-asserted-by":"crossref","first-page":"e0264407","DOI":"10.1371\/journal.pone.0264407","article-title":"Analysis of the complete lambda light chain germline usage in patients with AL amyloidosis and dominant heart or kidney involvement","volume":"17","year":"2022","journal-title":"PLoS One"},{"key":"2024091904052751000_2024.09.11.612490v1.59","doi-asserted-by":"publisher","DOI":"10.1515\/hsz-2016-0178"},{"key":"2024091904052751000_2024.09.11.612490v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.12.069"},{"key":"2024091904052751000_2024.09.11.612490v1.61","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21934"},{"key":"2024091904052751000_2024.09.11.612490v1.62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5446"},{"key":"2024091904052751000_2024.09.11.612490v1.63","first-page":"162","article-title":"Diagnostic tests: how to estimate the positive predictive value","volume":"2","year":"2015","journal-title":"Neurooncol Pract"},{"key":"2024091904052751000_2024.09.11.612490v1.64","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg8538"},{"key":"2024091904052751000_2024.09.11.612490v1.65","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2015.1.272"},{"key":"2024091904052751000_2024.09.11.612490v1.66","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.clml.2020.05.023","article-title":"AL Amyloidosis in Myeloma: Red Flag Symptoms","volume":"20","year":"2020","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"2024091904052751000_2024.09.11.612490v1.67","doi-asserted-by":"publisher","DOI":"10.4065\/mcp.2009.0547"},{"key":"2024091904052751000_2024.09.11.612490v1.68","doi-asserted-by":"crossref","unstructured":"Benson MD , Liepnieks JJ , Kluve-Beckerman B. Hereditary systemic immunoglobulin light-chain amyloidosis. Blood [Internet]. 2015; Available from: http:\/\/www.bloodjournal.org\/cgi\/doi\/10.1182\/blood-2014-12-618108.","DOI":"10.1182\/blood-2014-12-618108"},{"key":"2024091904052751000_2024.09.11.612490v1.69","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s42003-023-04574-y","article-title":"A constant domain mutation in a patient-derived antibody light chain reveals principles of AL amyloidosis","volume":"6","year":"2023","journal-title":"Commun Biol"},{"key":"2024091904052751000_2024.09.11.612490v1.70","doi-asserted-by":"publisher","DOI":"10.1021\/bi101351c"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.09.11.612490","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:03:22Z","timestamp":1768460602000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.09.11.612490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,15]]},"references-count":70,"URL":"https:\/\/doi.org\/10.1101\/2024.09.11.612490","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1080\/13506129.2024.2434899","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,9,15]]},"subtype":"preprint"}}