跟著城市嚮導「老臺北胃」，用味道認識臺北

很多朋友來臺北，
都會問我同一個問題：
「臺北小吃那麼多，到底該從哪裡開始吃？」
夜市裡攤位一字排開、老店藏在巷弄轉角，
看起來都很有名，卻又怕吃錯、踩雷，
結果行程走完，反而沒真正記住臺北的味道。
我常被朋友笑說是「老臺北胃」。
不是因為特別會吃，而是因為在這座城市待久了，
知道哪些味道是陪著臺北人成長的日常。
這篇文章，就是我整理的一份清單。
如果你第一次來臺北，
我會帶你從這 10 樣最具代表性的臺北小吃開始，
不追一時爆紅、不走浮誇路線，
而是讓你吃完後能真正理解
原來，這就是臺灣的小吃文化。
跟著老臺北胃走，
用最簡單的方式，
把臺北的味道，一樣一樣記在心裡。

我怎麼選出這 10 大臺北小吃？

在臺北，
你隨便走進一條夜市或老街，
都可以輕易列出 30 種以上的小吃。
所以這份清單，
不是「臺北最好吃」的排名，
 而是我站在「第一次來臺北的旅客」角度，
做的推薦。
身為一個被朋友稱作「老臺北胃」的人，
我選這 10 樣小吃時，心裡一直放著幾個原則。

一吃就知道：這就是臺灣味

燒烤、火鍋很好吃，
但換個城市、換個國家，也吃得到。
我挑的，是那種
只要一入口，就會讓人聯想到的臺灣味。
 不需要解釋太多，舌頭就能懂。

不只是好吃，而是有「臺北日常感」

臺北的小吃迷人，
不只在味道，
而在它融入生活的方式。
我在意的是：

1. 會不會出現在早餐、宵夜、下班後
2. 有沒有陪伴這座城市很久的記憶

吃完之後，你會記得臺北

最後一個標準很簡單。
如果你回到家，
還會突然想起某個味道、某碗熱湯、某個攤位的香氣
那它就值得被放進這份清單裡。

接下來的 10 樣臺北小吃，
就是我會親自帶朋友去吃的在地美食。
不趕行程、不拚數量，
而是一口一口，
慢慢認識臺北。

第 1 家：饌堂－黑金滷肉飯（雙連店）｜一碗就懂臺灣人的日常

如果只能用一道料理，
 來解釋臺灣人的日常飲食，
 那我一定會先帶你吃滷肉飯。
在臺北，滷肉飯不是什麼特別的節慶料理，
 而是從早餐、午餐到宵夜，
 默默陪著很多人長大的味道。
而在眾多滷肉飯之中，
饌堂－黑金滷肉飯（雙連店），
 我很常帶第一次來臺北的朋友造訪的一家。

為什麼第一站，我會選饌堂？
饌堂的滷肉飯，走的是**「黑金系」路線**。
滷汁顏色深、香氣厚，
卻不死鹹、不油膩。
滷肉切得細緻，
肥肉入口即化，搭配熱騰騰的白飯，
每一口都是很完整、很臺灣的味道。
對第一次吃滷肉飯的旅客來說，
這種風味夠經典、也夠穩定，
不需要太多心理準備，就能理解為什麼臺灣人這麼愛它。

不只是好吃，而是「現在的臺北感」
饌堂並不是那種躲在深巷裡的老攤，
空間乾淨、節奏俐落，
卻沒有失去滷肉飯該有的靈魂。
這也是我會推薦給旅客的原因之一：
它保留了臺灣小吃的核心味道，
同時也讓第一次來臺北的人，
吃得安心、坐得舒服。

老臺北胃的帶路小提醒
如果是第一次來：

1. 一定要點招牌黑金滷肉飯
   
2. 可以加一顆滷蛋，風味會更完整
3. 搭配簡單的小菜，就很有臺灣家常感

這不是那種吃完會驚呼「哇！」的料理，
而是會讓你在幾口之後，
慢慢理解
原來，臺灣人的日常，就是這樣被一碗飯照顧著。

地址：103臺北市大同區雙連街55號1樓

電話：0225501379

菜單：https://bio.site/ZhuanTang

第 2 家：富宏牛肉麵｜臺北深夜也醒著的一碗熱湯

如果說滷肉飯代表的是臺灣人的日常，
 那牛肉麵，
 就是很多臺北人心中最有份量的一餐。
而在臺北提到牛肉麵，
 富宏牛肉麵，
 幾乎是夜貓族、加班族、外地旅客一定會被帶去的一站。

為什麼老臺北胃會帶你來吃富宏？
富宏最讓人印象深刻的，
不是華麗裝潢，
而是那鍋永遠冒著熱氣的紅燒湯頭。
湯色濃而不混，
帶著牛骨與醬香慢慢熬出的厚度，
喝起來溫潤、不刺激，
卻會在嘴裡留下很深的記憶點。
牛肉給得大方，
燉到軟嫩卻不鬆散，
搭配彈性十足的麵條，
每一口都很直接、很臺北。

不分時間，任何時候都適合的一碗麵
富宏牛肉麵最迷人的地方，
在於它陪伴了無數個臺北的夜晚。
不管是深夜下班、看完演唱會、
或是剛抵達臺北、還沒適應時差，
這裡總有一碗熱湯在等你。
對旅客來說，
這種不用算時間、不用擔心打烊的安心感，
本身就是一種臺北特色。

老臺北胃的帶路小提醒
第一次來富宏，我會這樣點：

1. 紅燒牛肉麵是首選
   
2. 如果想吃得更過癮，可以加點牛筋或牛肚
3. 湯先喝一口原味，再視情況調整辣度

這不是精緻料理，
卻是一碗能在任何時刻撐住你的牛肉麵。
在臺北，
很多夜晚，
就是靠這樣一碗熱湯走過來的。

地址：108臺北市萬華區洛陽街67號

電話：0223713028

菜單：https://www.facebook.com/pages/富宏牛肉麵-原建宏牛肉麵/

第 3 家：士林夜市・吉彖皮蛋涼麵｜臺北夏天最有記憶點的一口清爽

如果你在夏天來到臺北，
 一定會很快發現一件事
 這座城市，真的很熱。
也正因為這樣，
 臺北的小吃世界裡，
 才會出現像「涼麵」這樣的存在。
而在士林夜市，
 吉彖皮蛋涼麵，
 就是我很常帶旅客來吃的一家。

為什麼在夜市，我會帶你吃涼麵？
很多人對夜市的印象，
都是炸物、熱湯、重口味。
但真正的臺北夜市，
其實也很懂得照顧人的胃。
吉彖的涼麵，
冰涼的麵條拌上濃郁芝麻醬，
再加上切得細緻的皮蛋，
入口的第一瞬間，
就是一種「被降溫」的感覺。
那種清爽，
不是沒味道，
而是在濃香與清涼之間取得剛剛好的平衡。

皮蛋，是靈魂，也是臺灣味的關鍵
對很多外國旅客來說，
皮蛋是既好奇、又有點猶豫的存在。
但我常說，
如果要嘗試皮蛋，
涼麵是一個非常溫柔的起點。
芝麻醬的香氣會先接住味蕾，
皮蛋的風味則在後段慢慢出現，
不衝、不嗆，
反而多了一層深度。
很多人吃完後，
都會露出那種「原來是這樣啊」的表情。

老臺北胃的帶路小提醒
第一次點吉彖皮蛋涼麵，我會建議：

1. 一定要選皮蛋款，才吃得到特色
2. 醬料先拌勻，再吃，風味會更完整
3. 如果天氣真的很熱，這一碗會救你一整晚

這不是華麗的小吃，
卻非常臺北。
在悶熱的夜晚，
站在夜市人潮裡，
吃著一碗涼麵，
你會突然明白——

原來臺北的小吃，連氣候都一起考慮進去了。

地址：111臺北市士林區基河路114號

電話：0981014155

菜單：https://www.facebook.com/profile.php?id=100064238763064

第 4 家：胖老闆誠意肉粥｜臺北人深夜最踏實的一碗粥

如果你問我，
 臺北人在深夜、下班後，
 最容易感到被安慰的食物是什麼——
 我會毫不猶豫地說：肉粥。
而提到肉粥，
 胖老闆誠意肉粥，
 就是很多老臺北人口中的那一味。

為什麼這一碗粥，會被叫做「誠意」？
胖老闆的肉粥，看起來很簡單。
白粥、肉燥、配菜，
沒有華麗擺盤，也沒有複雜作法。
但真正坐下來吃，你會發現：
這碗粥，不敷衍任何一個細節。
粥體滑順、不稀薄，
肉燥香而不膩，
搭配各式家常小菜，
一口一口吃下去，
很自然就會放慢速度。
這種味道，
不是要你驚艷，
而是要你安心。

這不是觀光小吃，而是臺北人的生活片段
胖老闆誠意肉粥，
最迷人的地方，
就是它的客人。
你會看到：

1. 剛下班的上班族
2. 熬夜後來吃一碗熱粥的人
3. 熟門熟路、點菜不用看菜單的老客人

這些畫面，
比任何裝潢都更能說明這家店在臺北的位置。
對旅客來說，
這是一個走進臺北人日常的入口。

老臺北胃的帶路小提醒
第一次來吃，我會這樣建議：

1. 肉粥一定要點，這是主角
2. 配幾樣小菜一起吃，才有完整體驗
3. 不用急，慢慢吃，這碗粥就是要你放鬆

這不是為了拍照而存在的小吃，
而是那種
**會讓人記得「那天晚上，我在臺北吃了一碗很溫暖的粥」**的味道。

地址：10491臺北市中山區長春路89-3號

電話：0913806139

菜單：https://lin.ee/xxbYZyS

第 5 家：圓環邊蚵仔煎｜夜市裡最不能缺席的臺灣經典

如果要選一道
 最常出現在旅客記憶裡的臺灣小吃，
 蚵仔煎一定排得上前幾名。
而在臺北，
 圓環邊蚵仔煎，
 就是那種很多臺北人從小吃到大的存在。

為什麼蚵仔煎，這麼能代表臺灣？
蚵仔煎的魅力，
不在於精緻，
而在於它把幾種看似簡單的食材，
煎成了一種獨特的口感。
新鮮蚵仔的海味、
雞蛋的香氣、
地瓜粉形成的滑嫩外皮，
最後再淋上甜中帶鹹的醬汁，
一口下去，
就是夜市的完整畫面。
這種味道，
很難在其他國家找到替代品。

圓環邊，吃的是記憶感
圓環邊蚵仔煎，
沒有多餘的包裝，
也不刻意迎合潮流。
它留下來的原因很簡單
味道夠穩、節奏夠快、
讓人一吃就知道「對，就是這個」。
對旅客來說，
這是一家
不需要研究、不需要比較，就能安心點蚵仔煎的地方。

老臺北胃的帶路小提醒
第一次吃蚵仔煎，我會這樣建議：

1. 趁熱吃，口感最好
   
2. 不用急著加辣，先吃原味
3. 醬汁是靈魂，別急著把它拌掉

蚵仔煎不是細嚼慢嚥的料理，
它屬於人聲鼎沸、鍋鏟作響的夜市時刻。
站在人群裡，
吃著一盤熱騰騰的蚵仔煎，
你會很清楚地感受到
這，就是臺北的夜晚。

地址：103臺北市大同區寧夏路46號

電話：0225580198

菜單：https://oystera.com.tw/menu

第 6 家：阿淑清蒸肉圓｜第一次吃肉圓，就該從這裡開始

說到臺灣小吃，
 很多人腦中一定會出現「肉圓」兩個字。
但真正吃過之後才會發現，
 肉圓，從來不只有一種樣子。
在臺北，
 阿淑清蒸肉圓，
 就是我很常拿來介紹「清蒸派肉圓」的一家。

清蒸肉圓，和你想像的不一樣
不少旅客對肉圓的第一印象，
來自油炸版本，
外皮厚、口感重。
而阿淑的清蒸肉圓，
完全是另一個方向。
外皮晶瑩、滑嫩，
帶著自然的彈性，
不油、不膩，
一入口反而顯得清爽。
內餡扎實，
豬肉香氣清楚，
搭配特製醬汁，
味道層次簡單卻很乾淨。

為什麼我會推薦給第一次來臺北的旅客？
因為這顆肉圓，
不需要適應期。
它不刺激、不厚重，
即使是第一次嘗試臺灣小吃的人，
也能輕鬆接受。
對旅客來說，
這是一顆
「吃得懂、也記得住」的肉圓。

老臺北胃的帶路小提醒
第一次來阿淑，我會這樣吃：

1. 直接點一顆清蒸肉圓，吃原味
2. 醬汁先別全部拌開，邊吃邊調整
3. 放慢速度，感受外皮的口感變化

這不是夜市裡熱鬧喧囂的料理，
而是那種
安靜地展現臺灣小吃功夫的味道。
當你吃完這顆肉圓，
會更明白一件事
臺灣小吃的魅力，
往往藏在這些細節裡。

地址：242新北市新莊區復興路一段141號

電話：0229975505

第 7 家：胡記米粉湯｜一碗最貼近臺北早晨的味道

如果說前面幾樣小吃，
 是臺北的熱鬧與記憶，
 那麼米粉湯，
 就是這座城市最真實的日常。
而在臺北，
 胡記米粉湯，
 是很多人從小吃到大的存在。

為什麼米粉湯，這麼「臺北」？
米粉湯不是重口味料理，
它靠的不是刺激，
而是一碗清澈卻有深度的湯。
胡記的湯頭，
用豬骨慢慢熬出香氣，
喝起來清爽、不油，
卻能在喉嚨留下溫度。
米粉細軟，
吸附湯汁後入口順滑，
簡單到不能再簡單，
卻正是臺北人習以為常的早晨風景。

配菜，才是這一碗的靈魂延伸
在胡記吃米粉湯，
主角雖然是湯，
但真正讓人滿足的，
往往是那些小菜。
紅燒肉、豬內臟、燙青菜，
隨意點上幾樣，
湯一口、菜一口，
就是很多臺北人記憶中的早餐組合。
對旅客來說，
這是一種
不需要解釋，就能融入的臺北生活感。

老臺北胃的帶路小提醒
第一次來胡記，我會這樣建議：

1. 一定要點米粉湯，湯先喝
2. 再配 1～2 樣小菜，體驗會完整很多
3. 這一餐適合慢慢吃，不用趕

這不是為了觀光而存在的小吃，
而是一碗
每天準時出現在臺北人生活裡的湯。
當你坐在店裡，
聽著湯勺碰撞的聲音，
你會突然感覺到——
原來，臺北的早晨，
就是從這樣一碗米粉湯開始的。

地址：106臺北市大安區大安路一段9號1樓

電話：0227212120

第 8 家：藍家割包｜一口咬下的臺灣街頭記憶

如果要選一道
 外國旅客一看到就會好奇、吃完又會記住的小吃，
 割包，一定在名單裡。
而在臺北，
 藍家割包，
 就是我很放心帶旅客來認識這道經典的一站。

割包，為什麼被叫做「臺灣漢堡」？
割包的結構其實很簡單：
鬆軟的白饅頭、
燉得入味的滷五花肉、
酸菜、花生粉、香菜。
但真正迷人的，
是這些元素組合在一起時，
形成的層次感。
肉香、甜味、鹹味、清爽度，
在一口之間同時出現，
沒有誰搶戲，
卻彼此剛好。
這種平衡感，
正是臺灣小吃很迷人的地方。

藍家割包不是走浮誇路線，
它給人的感覺很直接
就是你期待中的割包樣子。
饅頭柔軟不乾，
五花肉肥瘦比例恰到好處，
入口即化卻不膩口，
花生粉的甜香收尾，
讓整體味道非常完整。
對第一次吃割包的旅客來說，
這是一個
不會出錯、也很容易愛上的版本。

老臺北胃的帶路小提醒
第一次吃藍家割包，我會這樣建議：

1. 直接點招牌割包，不要改配料
2. 如果有香菜，建議保留，味道會更完整
3. 趁熱吃，饅頭口感最好

割包不是精緻料理，
卻非常有記憶點。
站在街頭，
拿著一顆熱騰騰的割包，
邊走邊吃，
你會很清楚地感受到
這一口，就是臺灣的街頭生活。

地址：100臺北市中正區羅斯福路三段316巷8弄3號

電話：0223682060

菜單：https://instagram.com/lan_jia_gua_bao?utm_medium=copy_link

第 9 家：御品元冰火湯圓｜臺北夜晚最溫柔的一碗甜

吃了一整天的臺北小吃，
 到了這個時候，
 胃其實已經差不多滿了。
但只要天氣一涼，
 或夜色慢慢降下來，
 你還是會想找一碗——
 不是為了吃飽，而是為了舒服的甜點。
這時候，我通常會帶你來 御品元冰火湯圓。

為什麼叫「冰火」？這碗湯圓的關鍵就在這裡
御品元最有特色的地方，
就在於它的「冰火交錯」。
熱騰騰的湯圓，
外皮軟糯、內餡濃香，
搭配冰涼清甜的桂花蜜湯，
一口下去，
溫度在嘴裡交替出現。
不是衝突，
而是一種很細膩的平衡。
這樣的吃法，
也正是臺灣甜點很擅長的地方——
不張揚，但很有記憶點。

這是一碗，會讓人慢下來的甜點
和夜市裡熱鬧的甜品不同，
御品元的冰火湯圓，
更像是一個讓人停下腳步的存在。
你會發現，
坐在這裡吃湯圓的人，
說話聲都會不自覺地變小。
對旅客來說，
這不只是吃甜點，
而是一個
把白天的熱鬧慢慢收進回憶裡的時刻。

老臺北胃的帶路小提醒
第一次吃御品元，我會這樣建議：

1. 點招牌冰火湯圓，體驗完整特色
2. 先單吃湯圓，再搭配湯一起吃
3. 放慢速度，這一碗不適合趕時間

這不是為了拍照而存在的甜點，
而是一碗
會讓你記得「那天晚上在臺北，很舒服」的湯圓。

地址：106臺北市大安區通化街39巷50弄31號

電話：0955861816

菜單：https://instagram.com/lan_jia_gua_bao

第 10 家：頃刻間綠豆沙牛奶專賣店｜把臺北的味道，留在最後一口清甜

走到這一站，
 其實已經不需要再吃什麼大份量的東西了。
這時候，
 最適合的，
 是一杯不吵鬧、不張揚，
 卻會默默留在記憶裡的飲品。
頃刻間綠豆沙牛奶，
 就是我很常用來替一天畫下句點的選擇。

綠豆沙牛奶，為什麼這麼「臺灣」？
在臺灣，
飲料不只是解渴，
而是一種生活節奏。
綠豆沙牛奶看起來簡單，
但真正好喝的版本，
靠的是火候、比例，
還有耐心。
頃刻間的綠豆沙，
口感細緻、不粗顆，
甜度自然、不膩口，
牛奶的加入，
讓整杯變得柔順而溫和。
這不是衝擊味蕾的飲料，
而是一種
喝完之後，會覺得剛剛那一刻很舒服的甜。

為什麼我會用它當作最後一站？
因為它很臺北。
你可以外帶，
邊走邊喝；
也可以站在店門口，
慢慢把杯子喝空。
沒有儀式感，
卻很真實。
對旅客來說，
這杯綠豆沙牛奶，
就像是把今天吃過的所有味道，
溫柔地整理好，
帶走。

老臺北胃的帶路小提醒
第一次喝頃刻間，我會這樣建議：

1. 直接點招牌綠豆沙牛奶
   
2. 正常甜就很剛好，不用特別調整
3. 找個角落慢慢喝，別急著趕路

這一杯，
不會讓你驚呼，
卻會在回程的路上，
突然想起來。
原來，臺北的味道，是這樣結束一天的。

地址：111臺北市士林區小北街1號

電話：0228818619

菜單：https://instagram.com/chill_out_moment?igshid=YmMyMTA2M2Y=

如果只有 3 天的自助旅行在臺北，怎麼吃這 10 家？

第一次來臺北，
時間有限、胃容量也有限，
與其每一家都趕，不如照著節奏吃。
這份 3 天小吃路線，
是老臺北胃會帶朋友實際走的版本：
不爆走、不硬塞，
讓你每天都吃得剛剛好。

臺北 3 天小吃推薦行程表（老臺北胃版本）

天數	時段	店家名稱	小吃類型
Day 1	午餐	饌堂－黑金滷肉飯（雙連店）	滷肉飯
Day 1	下午	阿淑清蒸肉圓	肉圓
Day 1	晚餐	富宏牛肉麵	牛肉麵
Day 1	宵夜	胖老闆誠意肉粥	粥品
Day 2	早餐	胡記米粉湯	米粉湯
Day 2	下午	藍家割包	割包
Day 2	晚上	士林夜市－吉彖皮蛋涼麵	涼麵
Day 2	夜市	圓環邊蚵仔煎	蚵仔煎
Day 3	下午	御品元冰火湯圓	甜點
Day 3	收尾	頃刻間綠豆沙牛奶專賣店	飲品

雖然每個小吃的地點都有一點距離，但是你也知道，好吃的小吃，是值得你花一點時間前往品嘗
老臺北胃的小提醒

1. 不需要每一家都點到最滿
2. 留一點餘裕，才會想再回來
3. 臺北小吃的魅力，不在於吃多少，而在於記住了什麼味道
   

當你照著這 3 天走完，
你會發現，
臺北不是靠一兩道名菜被記住的，
而是靠這些看似日常、卻很真實的小吃。
下次再來，老臺北胃再帶你吃更深的那一輪。

老臺北胃帶路｜這 10 口，就是我心中的臺北

寫到這裡，
 其實已經不是在推薦哪一家小吃了。
而是在回頭看，
 這座城市，是怎麼用食物陪著人生活的。
滷肉飯、牛肉麵、肉粥、米粉湯，
 不是為了成為觀光名單而存在，
 而是每天默默出現在臺北人的日子裡。
夜市裡的蚵仔煎、涼麵、割包，
 熱鬧、吵雜、節奏很快，
 卻也正是臺北最真實的樣子。
而最後那碗湯圓、那杯綠豆沙牛奶，
 則是在一天結束時，
 替味蕾留下一個溫柔的句點。

如果你問我，
「這 10 家是不是臺北最好吃的小吃？」
我會說，
它們不一定是排行榜第一名，
卻是我真的會帶朋友去吃的版本。
因為它們吃得到：

1. 臺北人的日常
2. 巷弄裡的熟悉感
3. 不需要解釋，就能被理解的味道

如果你是第一次來臺北，
跟著這份清單走，
你不一定會吃得最飽，
但你一定會記得——
臺北，是什麼味道。
而如果有一天，
你又再回到這座城市，
走進熟悉的街口、
看到冒著熱氣的小攤，
你也會開始懂得，
為什麼老臺北胃，
總是記得這些看似平凡的滋味。
因為，真正留在心裡的，
從來不是吃過多少，
而是哪一口，讓你想起臺北。

阿淑清蒸肉圓名過其實嗎？

走完這 10 家，

你可能會發現一件事饌堂－黑金滷肉飯（雙連店）辣的推薦嗎？

臺北的小吃，其實不急著被你記住。

它們就安靜地存在在街角、夜市、轉彎處，阿淑清蒸肉圓不加辣好吃嗎？

等你有一天，再回到這座城市。胖老闆誠意肉粥會不會太油？

如果你是第一次來臺北，胡記米粉湯怎麼點比較好？

希望這份「老臺北胃帶路」的清單，

能幫你少一點猶豫、多一點安心。

不用擔心踩雷，胖老闆誠意肉粥新手友善嗎？

也不用為了排行而奔波，頃刻間綠豆沙牛奶專賣店吃起來順口嗎？

只要照著節奏走，

你就會吃到屬於自己的臺北味道。

而如果你已經來過臺北，

那更希望這篇文章，阿淑清蒸肉圓推薦嗎？

能帶你走進那些

你可能錯過、卻一直都在的日常小吃。

因為真正迷人的旅行，

從來不是把清單全部打勾，

而是某一天，

你突然想起那碗飯、那口湯、那杯甜，頃刻間綠豆沙牛奶專賣店會不會太甜？

然後在心裡對自己說一句：圓環邊蚵仔煎會不會膩？

「下次再去臺北，還想再吃一次。」

把這篇文章存起來、分享給一起旅行的人，

或是在規劃行程時，再回來看看。

讓味道，成為你認識臺北的方式。

下一次來臺北，

別急著走遠。

老臺北胃，御品元冰火湯圓會不會太甜？

會一直在這些地方，

等你再回來。

Scientists have successfully sequenced the entire human Y chromosome, uncovering critical genomic features. This groundbreaking research offers deep insights into human biology and potential medical advancements. New sequence reveals genomic factors in fertility, including sperm production. An international research team has generated the first truly complete sequence of a human Y chromosome, the final human chromosome to be fully sequenced. The new sequence, which fills in gaps across more than 50% of the Y chromosome’s length, uncovers important genomic features with implications for fertility, such as factors in sperm production. The study, led by the Telomere-to-Telomere (T2T) Consortium, a team of researchers funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, will published today (August 23) in the journal Nature. The Y Chromosome’s Complex Roles The Y chromosome, along with the X chromosome, is often discussed for its role in sexual development. While these chromosomes play a central role, the factors involved in human sexual development are spread across the genome and very complex, giving rise to the array of human sex characteristics found among male, female, and intersex individuals. These categories are not equivalent to gender, which is a social category. Additionally, recent work demonstrates that genes on the Y chromosome contribute to other aspects of human biology, such as cancer risk and severity. The Y chromosome is the last of the 24 human chromosomes to be completely sequenced. Credit: Darryl Leja, National Human Genome Research Institute (NHGRI) Challenges in Y Chromosome Sequencing When researchers completed the first human genome sequence 20 years ago, gaps were left in the sequences of all 24 chromosomes. However, unlike the small gaps sprinkled across the rest of the genome sequence — gaps that the T2T Consortium filled in last year — over half of the Y chromosome’s sequence remained a mystery. All chromosomes have some repetitive regions, but the Y chromosome is unusually repetitive, making its sequence particularly difficult to complete. Assembling sequencing data is like trying to read a long book cut into strips. If all the lines in the book are unique, it’s easier to determine the order the lines go in. However, if the same sentence is repeated thousands or millions of times, the original order of the strips is far less clear. While all human chromosomes contain repeats, about 30 million letters of the Y chromosome are repetitive sequences. It’s as if the same few sentences were repeated for half the length of the book. Innovative Techniques Lead to Success To tackle the most repetitive pieces of the human genome, the T2T Consortium applied new DNA sequencing technologies and sequence assembly methods, as well as knowledge gained from generating the first gapless sequences for the other 23 human chromosomes. “The biggest surprise was how organized the repeats are,” said Adam Phillippy, Ph.D., a senior investigator at NHGRI and leader of the consortium. “We didn’t know what exactly made up the missing sequence. It could have been very chaotic, but instead, nearly half of the chromosome is made of alternating blocks of two specific repeating sequences known as satellite DNA. It makes a beautiful, quilt-like pattern.” Medical Relevance and Future Research The complete Y chromosome sequence also reveals important features of medically relevant regions. One such section of the Y chromosome is called the azoospermia factor region, a stretch of DNA containing several genes known to be involved in sperm production. With the newly completed sequence, the researchers studied the structure of a set of inverted repeats or “palindromes” in the azoospermia factor region. “This structure is very important because occasionally these palindromes can create loops of DNA,” said Arang Rhie, Ph.D., NHGRI staff scientist and first author of the Nature publication. “Sometimes, these loops accidentally get cut off and create deletions in the genome.” Deletions in the azoospermia factor region are known to disrupt sperm production, and thus these palindromes could influence fertility. With a complete Y chromosome sequence, researchers can now more precisely analyze these deletions and their effects on sperm production. Other regions with potential medical relevance contain genes that repeat. Most genes in the human genome have two copies, one inherited from each parent. However, some genes have many copies that repeat along a stretch of DNA, sometimes referred to as a “gene array.” The researchers focused on TSPY, another gene thought to be involved in sperm production. Copies of TSPY are organized in the second largest gene array in the human genome. Like other repetitive regions, repeating genes are challenging to analyze, so while TSPY was known to exist as many repeating copies, the specific DNA sequence and organization of this array was previously unknown. As the researchers analyzed this region, they found that different individuals contained between 10 and 40 copies of TSPY. “When you find variation that you haven’t seen before, the hope is always that those genomic variants will be important for understanding human health,” said Dr. Phillippy. “Medically relevant genomic variants can help us design better diagnostics in the future.” For more on this research, see The Full Story Behind Sequencing Humanity’s Most Elusive Chromosome. Reference: “The complete sequence of a human Y chromosome” by Arang Rhie, Sergey Nurk, Monika Cechova, Savannah J. Hoyt, Dylan J. Taylor, Nicolas Altemose, Paul W. Hook, Sergey Koren, Mikko Rautiainen, Ivan A. Alexandrov, Jamie Allen, Mobin Asri, Andrey V. Bzikadze, Nae-Chyun Chen, Chen-Shan Chin, Mark Diekhans, Paul Flicek, Giulio Formenti, Arkarachai Fungtammasan, Carlos Garcia Giron, Erik Garrison, Ariel Gershman, Jennifer L. Gerton, Patrick G. S. Grady, Andrea Guarracino, Leanne Haggerty, Reza Halabian, Nancy F. Hansen, Robert Harris, Gabrielle A. Hartley, William T. Harvey, Marina Haukness, Jakob Heinz, Thibaut Hourlier, Robert M. Hubley, Sarah E. Hunt, Stephen Hwang, Miten Jain, Rupesh K. Kesharwani, Alexandra P. Lewis, Heng Li, Glennis A. Logsdon, Julian K. Lucas, Wojciech Makalowski, Christopher Markovic, Fergal J. Martin, Ann M. Mc Cartney, Rajiv C. McCoy, Jennifer McDaniel, Brandy M. McNulty, Paul Medvedev, Alla Mikheenko, Katherine M. Munson, Terence D. Murphy, Hugh E. Olsen, Nathan D. Olson, Luis F. Paulin, David Porubsky, Tamara Potapova, Fedor Ryabov, Steven L. Salzberg, Michael E. G. Sauria, Fritz J. Sedlazeck, Kishwar Shafin, Valery A. Shepelev, Alaina Shumate, Jessica M. Storer, Likhitha Surapaneni, Angela M. Taravella Oill, Françoise Thibaud-Nissen, Winston Timp, Marta Tomaszkiewicz, Mitchell R. Vollger, Brian P. Walenz, Allison C. Watwood, Matthias H. Weissensteiner, Aaron M. Wenger, Melissa A. Wilson, Samantha Zarate, Yiming Zhu, Justin M. Zook, Evan E. Eichler, Rachel J. O’Neill, Michael C. Schatz, Karen H. Miga, Kateryna D. Makova and Adam M. Phillippy, 23 August 2023, Nature. DOI: 10.1038/s41586-023-06457-y Recent Advances in Genomic Research In addition to the complete Y chromosome sequence, the NHGRI-funded Human Genome Structural Variation Consortium reports the sequence of 43 diverse human Y chromosomes, also published today in the same issue of Nature. These advances complement the gapless human genome sequence released by the T2T Consortium in 2022, as well as the “pangenome” released in May of 2023 by the NHGRI-funded Human Pangenome Reference Consortium. Through these achievements, scientists have access to an abundance of new genomics resources to unravel human biology and pave the way for the future of genomic medicine.

New research from the University of California, San Francisco and Stanford Medicine is challenging the long-held belief that the receptor for oxytocin, known as the “love hormone,” is essential for forming social bonds. The study, published in the journal Neuron, found that prairie voles bred without oxytocin receptors showed similar monogamous mating, attachment, and parenting behaviors to regular voles, and even gave birth and produced milk albeit in smaller quantities. This contradicts the previous idea that oxytocin is critical to these social behaviors and raises new questions about the role of the hormone in bonding. Removing the Oxytocin Receptor Does Not Interfere with Monogamy or Giving Birth Turning a decades-old dogma on its head, new research from scientists at University of California, San Francisco and Stanford Medicine shows that the receptor for oxytocin, a hormone considered essential to forming social bonds, may not play the critical role that scientists have assigned to it for the past 30 years. In the study, published on January 27, 2023, in the journal Neuron, the team found that prairie voles bred without receptors for oxytocin and showed the same monogamous mating, attachment, and parenting behaviors as regular voles. In addition, females without oxytocin receptors gave birth and produced milk, though in smaller quantities, than ordinary female voles. The results indicate that the biology underlying pair bonding and parenting isn’t purely dictated by the receptors for oxytocin, sometimes referred to as the “love hormone.” “While oxytocin has been considered ‘Love Potion #9,’ it seems that potions 1 through 8 might be sufficient,” said psychiatrist Devanand Manoli, MD, PhD, a senior author of the paper and member of the UCSF Weill Institute for Neurosciences. “This study tells us that oxytocin is likely just one part of a much more complex genetic program.” This is a photograph of two prairie voles. Credit: Nastacia Goodwin CRISPR Voles Pack a Surprise Because prairie voles are one of the few mammalian species known to form lifelong monogamous relationships, researchers study them to better understand the biology of social bonding. Studies in the 1990s using drugs that prevent oxytocin from binding to its receptor found that voles were unable to pair bond, giving rise to the idea that the hormone is essential to forming such attachments. The current project emerged from shared interests between Manoli and co-senior author and neurobiologist Nirao Shah, MD, PhD, then at UCSF and now at Stanford Medicine. Shah had been interested in the biology of oxytocin and social attachment in prairie voles since teaching about the oxytocin studies decades earlier. Manoli, who wanted to investigate the neurobiology of social bonding, joined Shah’s lab in 2007 as a postdoctoral scholar. For this study, 15 years in the making, the two applied new genetic technologies to confirm if oxytocin binding to its receptor was indeed the factor behind pair bonding. They used CRISPR to generate prairie voles that lack functional oxytocin receptors. Then, they tested the mutant voles to see whether they could form enduring partnerships with other voles. To the researchers’ surprise, the mutant voles formed pair bonds just as readily as normal voles. “The patterns were indistinguishable,” said Manoli. “The major behavioral traits that were thought to be dependent on oxytocin – sexual partners huddling together and rejecting other potential partners as well as parenting by mothers and fathers – appear to be completely intact in the absence of its receptor.” Labor and Lactation Even more surprising for Manoli and Shah than the pair bonding was the fact that a significant percentage of the female voles were able to give birth and provide milk for their pups. Oxytocin is likely to have a role in both birth and lactation, but one that is more nuanced than previously thought, Manoli said. Female voles without receptors proved perfectly capable of giving birth, on the same timeframe and in the same way as the regular animals, even though labor has been thought to rely on oxytocin. The results help to clear up some of the mystery surrounding the hormone’s role in childbirth: Oxytocin is commonly used to induce labor but blocking its activity in mothers who experience premature labor isn’t better than other approaches for halting contractions. When it came to producing milk and feeding pups, however, the researchers were taken aback. Oxytocin binding to its receptor has been considered essential for milk ejection and parental care for many decades, but half of the mutant females were able to nurse and wean their pups successfully, indicating that oxytocin signaling plays a role, but it is less vital than previously thought. “This overturns conventional wisdom about lactation and oxytocin that’s existed for a much longer time than the pair bonding association,” said Shah. “It’s a standard in medical textbooks that the milk letdown reflex is mediated by the hormone, and here we are saying, ‘Wait a second, there’s more to it than that.’” Hope for Social Connection Manoli and Shah focused on understanding the neurobiology and molecular mechanisms of pair bonding because it is thought to hold the key to unlocking better treatments for psychiatric conditions, such as autism and schizophrenia, that interfere with a person’s ability to form or maintain social bonds. Over the past decade, much hope was pinned on clinical trials using oxytocin to address those conditions. But those results were mixed, and none has illuminated a clear path to improvement. The researchers said their study strongly suggests that the current model – a single pathway or molecule being responsible for social attachment –is oversimplified. This conclusion makes sense from an evolutionary perspective, they said, given the importance of attachment to the perpetuation of many social species. “These behaviors are too important to survival to hinge on this single point of potential failure,” said Manoli. “There are likely other pathways or other genetic wiring to allow for that behavior. Oxytocin receptor signaling could be one part of that program, but it’s not the be-all end-all.” The discovery points the researchers down new paths to improving the lives of people struggling to find social connection. “If we can find the key pathway that mediates attachment and bonding behavior,” Shah said, “We’ll have an eminently druggable target for alleviating symptoms in autism, schizophrenia, many other psychiatric disorders.” For more on this research, see Were We Wrong About the “Love Hormone” Oxytocin? Reference: “Oxytocin receptor is not required for social attachment in prairie voles” by Kristen M. Berendzen, Ruchira Sharma, Maricruz Alvarado Mandujano, Yichao Wei, Forrest D. Rogers, Trenton C. Simmons, Adele M.H. Seelke, Jessica M. Bond, Rose Larios, Nastacia L. Goodwin, Michael Sherman, Srinivas Parthasarthy, Isidero Espineda, Joseph R. Knoedler, Annaliese Beery, Karen L. Bales, Nirao M. Shah and Devanand S. Manoli, 27 January 2023, Neuron. DOI: 10.1016/j.neuron.2022.12.011 Additional authors include: Ruchira Sharma, Rose Larios, Nastacia Goodwin, Michael Sherman and Isidero Espineda of UCSF, Maricruz Alvarado Mandujano, YiChao Wei, Srinivas Parthasarthy and Joseph Knoedler of Stanford, and Forrest Rogers, Trenton Simmons, Adele Seelke, Jessica Bond, and Karen Bales of UC Davis, and Annaliese Beery of UC Berkeley. This work was supported by NIH grants R01MH123513, R01MH108319, DP1MH099900 and R25MH060482, NSF grant, 1556974, and philanthropy. For details, see the study.

The microprotein in the mitochondria (green) and in the nucleus (blue) was overexpressed in human cells. The yellow and pink areas show that the signal of the microprotein overlaps with the mitochondrial and nuclear signals. Credit: Clara Sandmann, Max Delbrück Center A new study has overturned the notion that microproteins, small proteins previously deemed unimportant, play no significant role in human cellular functions. The research, led by Professor Norbert Hübner and Dr. Sebastiaan van Heesch, has shown that these proteins, primarily found in humans, interact with larger, older proteins and play a key role in evolutionary development. The research also unveiled the smallest human proteins known, with potential implications for diseases like cardiovascular disease and cancer. Every biologist knows that small structures can sometimes have a big impact: Millions of signaling molecules, hormones, and other biomolecules are bustling around in our cells and tissues, playing a leading role in many of the key processes occurring in our bodies. Yet despite this knowledge, biologists and physicians long ignored a particular class of proteins – their assumption being that because the proteins were so small and only found in primates, they were insignificant and functionless. The discoveries made by Professor Norbert Hübner at the Max Delbrück Center and Dr. Sebastiaan van Heesch at the Princess Máxima Center for Pediatric Oncology in the Netherlands changed this view a few years ago: “We were the first to prove the existence of thousands of new microproteins in human organs,” says Hübner. In a paper that was recently published in the journal Molecular Cell, the team led by Hübner and van Heesch now describe how they systematically studied these miniproteins, and what they learned from them: “We were able to show which genome sequences the proteins are encoded in, and when DNA mutations occurred in their evolution,” explains Dr. Jorge Ruiz-Orera, an evolutionary biologist in Hübner’s lab and one of the paper’s three lead authors, who work at the Max Delbrück Center and the German Center for Cardiovascular Research (DZHK). Ruiz-Orera’s bioinformatic gene analyses revealed that most human microproteins developed millions of years later in the evolutionary process than the larger proteins currently known to scientists. Yet the huge age gap doesn’t appear to prevent the proteins from “talking” to each other. “Our lab experiments showed that the young and old proteins can bind to each other – and in doing so possibly influence each other,” says lead author Dr. Jana Schulz, a researcher in Hübner’s team and at the DZHK. She, therefore, suspects that, contrary to long-held assumptions, the microproteins play a key role in a variety of cellular functions. The young proteins might also be heavily involved in evolutionary development thanks to comparatively rapid “innovations and adaptations.” “It’s possible that evolution is more dynamic than previously thought,” says van Heesch. Proteins Only Found in Humans The researchers were surprised to find that the vastly younger microproteins could interact with the much older generation. This observation came from experiments performed using a biotechnical screening method developed at the Max Delbrück Center in 2017. In collaboration with Dr. Philipp Mertins and the Proteomics Platform, which the Max Delbrück Center operates jointly with the Berlin Institute of Health at Charité (BIH), the miniproteins were synthesized on a membrane and then incubated with a solution containing most of the proteins known to exist in a human cell. Sophisticated experimental and computer-aided analyses then allowed the researchers to identify individual binding pairs. “If a microprotein binds to another protein, it doesn’t necessarily mean that it will influence the workings of the other protein or the processes that the protein is involved in,” says Schulz. However, the ability to bind does suggest the proteins might influence each other’s functioning. Initial cellular experiments conducted at the Max Delbrück Center in collaboration with Professors Michael Gotthardt and Thomas Willnow confirm this assumption. This leads Ruiz-Orera to suspect that the microproteins “could influence cellular processes that are millions of years older than they are, because some old proteins were present in the very earliest life forms.” Unlike the known, old proteins that are encoded in our genome, most microproteins emerged more or less “out of nowhere – in other words, out of DNA regions that weren’t previously tasked with producing proteins,” says Ruiz-Orera. Microproteins, therefore, didn’t take the “conventional” and much easier route of being copied and derived from existing versions. And because these small proteins only emerged during human evolution, they are missing from the cells of most other animals, such as mice, fish and birds. These animals, however, have been found to possess their own collection of young, small proteins. The Smallest Proteins So Far During their work, the researchers also discovered the smallest human proteins identified to date: “We found over 200 super-small proteins, all of which are smaller than 16 amino acids,” says Dr. Clara Sandmann, the study’s third lead author. Amino acids are the sole building blocks of proteins. Sandmann says this raises the question of how small a protein can be – or rather, how big it must be to be able to function. Usually, proteins consist of several hundred amino acids. The small proteins that were already known to scientists are known as peptides and function as hormones or signal molecules. They are formed when they split off from larger precursor proteins. “Our work now shows that peptides of a similar size can develop in a different way,” says Sandmann. These smallest-of-the-small proteins can also bind very specifically to larger proteins – but it remains unclear whether they can become hormones or similar: “We don’t yet know what most of these microproteins do in our body,” says Sandmann. Yet the study does provide an inkling of what the molecules are capable of: “These initial findings open up numerous new research opportunities,” says van Heesch. Clearly, the microproteins are much too important for researchers to keep ignoring them. Van Heesch says the biomolecular and medical research communities are very enthusiastic about these new findings. One conceivable scenario would be “that these microproteins are involved in cardiovascular disease and cancer, and could therefore be used as new targets for diagnostics and therapies,” says Hübner. Several U.S. biotech companies are already doing research in this direction. And the team behind the current paper also has big plans: Their study investigated 281 microproteins, but the aim now is to expand the experiments to include many more of the 7,000 recently cataloged microproteins – in the hope that this will reveal many as-yet-undiscovered functions. Reference: “Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames” by Clara-L. Sandmann, Jana F. Schulz, Jorge Ruiz-Orera, Marieluise Kirchner, Matthias Ziehm, Eleonora Adami, Maike Marczenke, Annabel Christ, Nina Liebe, Johannes Greiner, Aaron Schoenenberger, Michael B. Muecke, Ning Liang, Robert L. Moritz, Zhi Sun, Eric W. Deutsch, Michael Gotthardt, Jonathan M. Mudge, John R. Prensner, Thomas E. Willnow, Philipp Mertins, Sebastiaan van Heesch and Norbert Hubner, 17 February 2023, Molecular Cell. DOI: 10.1016/j.molcel.2023.01.023

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